Method of inhibiting amyloid protein aggregation and imaging amyloid deposits

ABSTRACT

The present invention provides a method of treating Alzheimer&#39;s disease using a compound of Formula I  
                 
 
     Also provided is a method of inhibiting the aggregation of amyloid proteins using a compound of Formula I and a method of imaging amyloid deposits, as well as new compounds of Formula I.

FIELD OF THE INVENTION

[0001] This invention relates to a method of inhibiting amyloid proteinaggregation and imaging amyloid deposits. More particularly, thisinvention relates to a method of inhibiting amyloid protein aggregationin order to treat Alzheimer's disease.

BACKGROUND OF THE INVENTION

[0002] Amyloidosis is a condition characterized by the accumulation ofvarious insoluble, fibrillar proteins in the tissues of a patient. Thefibrillar proteins that comprise the accumulations or deposits arecalled amyloid proteins. While the particular proteins or peptides foundin the deposits vary, the presence of fibrillar morphology and a largeamount of 5-sheet secondary structure is common to many types ofamyloids. An amyloid deposit is formed by the aggregation of amyloidproteins, followed by the further combination of aggregates and/oramyloid proteins.

[0003] The presence of amyloid deposits has been shown in variousdiseases, each with its particular associated protein, such asMediterranean fever, Muckle-Wells syndrome, idiopathetic myeloma,amyloid polyneuropathy, amyloid cardiomyopathy, systemic senileamyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage withamyloidosis, Alzheimer's disease, Down's syndrome, Scrapie,Creutzfeldt-Jacob disease, Kuru, Gerstmann-Straussler-Scheinkersyndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid,β₂-microglobulin amyloid in dialysis patients, inclusion body myositis,β₂-amyloid deposits in muscle wasting disease, Sickle Cell Anemia,Parkinson's Disease, and Islets of Langerhans diabetes Type IIinsulinoma.

[0004] Alzheimer's disease is a degenerative brain disordercharacterized clinically by progressive loss of memory, cognition,reasoning, judgement, and emotional stability that gradually leads tomental deterioration and ultimately death. Because Alzheimer's diseaseand related degenerative brain disorders are a major medical issue foran increasingly aging population, the need for new treatments andmethods for diagnosing the disorders are needed.

[0005] A simple, noninvasive method for detecting and quantitatingamyloid deposits in a patient has been eagerly sought. Presently,detection of amyloid deposits involves histological analysis of biopsyor autopsy materials. Both methods have major drawbacks. For example, anautopsy can only be used for a postmortem diagnosis.

[0006] The direct imaging of amyloid deposits in vivo is difficult, asthe deposits have many of the same physical properties (i.e., densityand water content) as normal tissues. Attempts to image amyloid depositsdirectly using magnetic resonance imaging (MRI) and computer-assistedtomography (CAT) have been disappointing and have detected amyloiddeposits only under certain favorable conditions. In addition, effortsto label amyloid deposits with antibodies, serum amyloid P protein, orother probe molecules has provided some selectivity on the periphery oftissues, but has provided for poor imaging of tissue interiors.

[0007] Thus, it would be useful to have a noninvasive technique forimaging and quantitating amyloid deposits in a patient. In addition, itwould be useful to have compounds that inhibit the aggregation ofamyloid proteins to form amyloid deposits.

SUMMARY OF THE INVENTION

[0008] The present invention provides a method of treating Alzheimer'sdisease, the method comprising administering to a patient havingAlzheimer's disease a therapeutically effective amount of a compound ofFormula I

[0009] wherein

[0010] R^(a) is hydrogen, C₁-C₆ alkyl, or

[0011] n is 0 to 5 inclusive;

[0012] R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are independently hydrogen,halogen, —OH, —NH₂, NR^(b)R^(c), —CO₂H, —CO₂C₁-C₆ alkyl, —NO₂, —OC₁-C₁₂alkyl, —C₁-C₈ alkyl, —CF₃, —CN, —OCH₂ phenyl, —OCH₂-substituted phenyl,—(CH₂)_(m)-phenyl, —O-phenyl, —O-substituted phenyl, —CH═CH-phenyl,—O(CH₂)_(p)NR^(b)R^(c),

[0013]  —NH(CH₂)_(p)NR^(b)R^(c), —N(C₁-C₆alkyl)(CH₂)_(p)NR^(b)R^(c),

[0014] R⁸ is COOH, tetrazolyl, —SO₂R^(d), or —CONHSO₂R^(d);

[0015] R^(b) and R^(c) are independently hydrogen, —C₁-C₆ alkyl,—(CH₂)_(m)-phenyl, or R^(b) and R^(c) taken together with the nitrogenatom to which they are attached form a cyclic ring selected frompiperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C₁-C₆alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, orpyrazolyl;

[0016] R^(d) is hydrogen, —C₁-C₆ alkyl, —CF₃, or phenyl;

[0017] m is 0 to 5 inclusive;

[0018] p is 1 to 5 inclusive;

[0019] A is CH or N;

[0020] R¹ and R², when adjacent to one another, can be methylene-dioxy;

[0021] or the pharmaceutically acceptable salts thereof.

[0022] In a preferred embodiment, the

[0023] group is attached at the 4-position of the phenyl ring.

[0024] In a preferred embodiment of the method, in the compounds ofFormula I

[0025] R^(a) is hydrogen;

[0026] n is 2; and

[0027] R³ and R⁴ are hydrogen.

[0028] In a preferred embodiment of the method, in the compounds ofFormula I

[0029] R^(a) is hydrogen;

[0030] R¹ is halo;

[0031] R² is hydrogen or halo;

[0032] R³, R⁴, R⁵, and R⁶ are hydrogen; and

[0033] n is 2 to 5 inclusive.

[0034] In another preferred embodiment of the method, in the compoundsof Formula I

[0035] R^(a) is hydrogen;

[0036] n is 2 or 3;

[0037] R¹ is —NR^(b)R^(c); and

[0038] R², R³, R⁴, R⁵, and R⁷ all are hydrogen.

[0039] In a preferred embodiment of the method, in the compounds ofFormula I

[0040] R^(a) is hydrogen;

[0041] n is 2;

[0042] R³ and R⁴ are hydrogen; and

[0043] R¹, R², and R⁷ are independently chlorine, —N(CH₂CH₃)₂, —OH,CH₃—, fluorine, —CF₃, phenyl, hydrogen, —OCH₂ phenyl, —O(CH₂)₃N(CH₃)₂,—O phenyl, —O(CH₂)₇CH₃, —CH(CH₂OCH₂CH₃)₂, pyrrolyl, —CH═CH-phenyl,

[0044]  —N[(CH₂)₃CH₃]₂, substituted phenyl, —OCH₂-substituted phenyl,pyrrozolyl, or —N(phenyl)₂.

[0045] In a preferred embodiment of the method, in the compounds ofFormula I

[0046] R^(a) is hydrogen;

[0047] n is 3, 4, or 5;

[0048] R³ and R⁴ are hydrogen; and

[0049] R¹, R², and R⁷ are independently chlorine or hydrogen.

[0050] In a preferred embodiment of the method, in the compounds ofFormula I

[0051] R^(a) is hydrogen;

[0052] n is 2;

[0053] R³ and R⁴ are hydrogen; and

[0054] R⁵, R⁶, and R⁸ are independently hydrogen, —CO₂H, —NO₂, —OCH₃,imidazolyl,

[0055]  fluorine, —CH₃, —CF₃, halogen, —NH—C₁-C₆ alkyl, —N(C₁-C₆alkyl)₂,—NH₂, or pyrrolyl.

[0056] In a preferred embodiment of the method, in the compounds ofFormula I

[0057] R^(a) is hydrogen;

[0058] n is 2;

[0059] R³ and R⁴ are hydrogen; and

[0060] R⁵ is —CO₂H.

[0061] Also preferred is a method of treating Alzheimer's disease, themethod comprising administering to a patient having Alzheimer's diseasea therapeutically effective amount of a compound of Formula I

[0062] wherein

[0063] R^(a) is hydrogen;

[0064] n is 1 to 5 inclusive;

[0065] R³ and R⁴ are hydrogen;

[0066] R¹, R⁷, and R² are independently chlorine, —N(CH₂CH₃)₂, —OH,CH₃—, fluorine, —CF₃, phenyl, hydrogen, —OCH₂ phenyl, —O(CH₂)₃N(CH₃)₂,—O phenyl, —O(CH₂)₇CH₃, —CH(CH₂OCH₂CH₃)₂, pyrrolyl, —CH═CH-phenyl,—N[(CH₂)₃CH₃]₂, substituted phenyl, —OCH₂-substituted phenyl, pyrazolyl,or —N(phenyl)₂;

[0067] R⁵ and R⁶ are independently hydrogen, —CO₂H, —NO₂, —OCH₃,imidazolyl, —CN, fluorine, —CH₃, —CF₃, or pyrrolyl;

[0068] or the pharmaceutically acceptable salts thereof.

[0069] In a preferred embodiment of the method, compounds of Formula Iare

[0070] 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid;

[0071] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid;

[0072]2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino}4-methoxy-5-nitrobenzoicacid;

[0073] 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid;

[0074] 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid;

[0075] 2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid;

[0076]2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoicacid;

[0077]2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}4-imidazo-1-yl-5-nitrobenzoicacid;

[0078] 2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino}benzoic acid;

[0079] 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid;

[0080] 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoicacid;

[0081]2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}-3,5-dinitrobenzoic acid;

[0082] 2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoicacid;

[0083]2-{4-[5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoicacid;

[0084] 2-[4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid;

[0085] 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid;

[0086] 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid;

[0087]2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0088] 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid;

[0089] 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid;

[0090] 2-(4-Phenethyl-phenylamino)-benzoic acid;

[0091]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoicacid;

[0092] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-terephthalicacid;

[0093]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid;

[0094] 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalicacid;

[0095]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methanesulfonyl-benzoicacid;

[0096]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-imidazol-1-yl-benzoicacid;

[0097] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro-benzoicacid;

[0098] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-nitro-benzoicacid;

[0099] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-nitro-benzoicacid;

[0100] 5-Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0101]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}4,6-difluoro-benzoicacid;

[0102]6-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-2,3-difluoro-benzoicacid;

[0103]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-fluoro-benzoic acid;

[0104]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-fluoro-benzoic acid;

[0105] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-methyl-benzoic acid;

[0106] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}4-fluoro-benzoicacid;

[0107]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3,5-difluoro-benzoicacid;

[0108]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-trifluoromethyl-benzoicacid;

[0109]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-trifluoromethyl-benzoicacid;

[0110]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid;

[0111]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-pyrrol-1-yl-benzoicacid;

[0112] 2-{4-[2-(4-Benzyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0113]2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0114] 2-{4-[2-(4-Diethylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0115] 2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0116] 2-{4-[2-(4-Octyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0117]2-(4-{2-[4-(2-Ethoxy-1-ethoxymethyl-ethyl)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0118] 2-{4-[2-(4-Pyrrol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0119] 2-{4-[2-(4-Styryl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0120] 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0121] 2-{4-[2-(4′-Ethyl-biphenyl-4-yl)-ethyl]-phenylamino}-benzoicacid;

[0122] 2-{4-[2-(4-Octyl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0123]2-(4-{2-[3-(3,5-Dichloro-phenoxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0124]2-(4-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0125] 2-{4-[2-(4-Pyrazol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0126] 2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0127]2-(4-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0128] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-amino-benzoicacid;

[0129]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid;

[0130] 2-{4-[2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid;

[0131] 2-{4-[2-[(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoicacid;

[0132] 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid;

[0133]2-[[4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]phenyl]amino-benzoicacid;

[0134] 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid;

[0135] 2-{4-[3-(4-Nitrophenyl)propyl]phenylamino}benzoic acid;

[0136] 2-{4-[3-(3-Nitrophenyl)propyl]phenylamino}benzoic acid;

[0137] 2-{4-[3-(4-Aminophenyl)propyl]phenylamino}benzoic acid;

[0138] 2-{4-[3-(3-Aminophenyl)propyl]phenylamino}benzoic acid;

[0139] 2-{4-[2-(4-Aminophenyl)ethyl]phenylamino}benzoic acid;

[0140] 2-{4-[2-(4-Dipropylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0141] 2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride monohydrate;

[0142] 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenylamino}benzoic acid;

[0143] 2-{4-[3-(3-Dimethylaminophenyl)propyl]phenylamino}benzoic acid;

[0144] 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoic acid;

[0145]2-(N-{4-[3-(4-Diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoicacid;

[0146] 2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino}benzoic acid;

[0147] 2-{4-[3-(3-Diethylaminophenyl)propyl]phenylamino}benzoic acid;

[0148] 2-{4-[2-(3-Aminophenyl)ethyl]phenylamino}benzoic acid;

[0149] 2-{4-[3-(4-Dimethylaminophenyl)propyl]phenylamino}benzoic acid;

[0150] 2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino}benzoic acid;

[0151] 2-{4-[2-(3-Acetylaminophenyl)ethyl]phenylamino}benzoic acid;

[0152] 2-{4-[2-(3-Dipropylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0153] 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0154] 2-{4-[3-(4-Acetylaminophenyl)propyl]phenylamino}benzoic acid;

[0155] 2-{4-[3-(3-Acetylaminophenyl)propyl]phenylamino}benzoic acid;

[0156] 2-{4-[3-(3-Diethylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochworide;

[0157] 2-{4-[2-(3-Piperidin-1-ylphenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0158] 2-{4-[3-(4-Dipropylaminophenyl)propyl]phenylamino}benzoic acid;

[0159] 2-{4-[3-(4-Dibutyl aminophenyl)propyl]phenylamino}benzoic acid;

[0160] 2-{4-[3-(3-Dibutylaminophenyl)propyl]phenylamino}benzoic acid;

[0161] 2-(4-{3-[4-(1H-Pyrrol-1-yl)phenyl]propyl}phenylamino) benzoicacid;

[0162] 2-{4-[3-(4-Piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid;

[0163] 2-{4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino}benzoicacid;

[0164] 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino}benzoic acid;

[0165] 2-{4-[3-(4-Diethylaminomethylphenyl)propyl]phenylamino}benzoicacid;

[0166] 2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino}benzoic acid;

[0167] 2-{4-[3-(3-Propylaminophenyl)propyl]phenylamino}benzoic acid;

[0168] 2-{4-[3-(4-Pyrrolidin-1-yl-phenyl)-propyl]-phenylamino}-benzoicacid;

[0169] 2-{4-[3-(3-Piperidin-1-yl-phenyl)-propyl]-phenylamino}-benzoicacid;

[0170] 2-{4-[3-(4-[2-Diethylaminoethylamino]phenyl)-propyl]phenylamino}-benzoic acid;

[0171]2-{4-[2-(4-[Hydroxycarbonylmethylamino]phenyl)ethyl]phenylamino}benzoicacid;

[0172]2-{4-[2-(4-[2-Diethylamrinoethylamino]phenyl)ethyl]phenylamino}-benzoicacid;

[0173] 2-{4-[3-(4-Morpholinophenyl)propyl]phenylamino}-benzoic acid;

[0174] 2-{4-[3-(4-piperazinylphenyl)propyl]phenylamino}-benzoic acid;and

[0175] 2-[4-(3,4-Dichlorophenyl)phenylamino]benzoic acid.

[0176] The invention also provides the foregoing compounds wherein thebenzoic acid portion is replaced with a pyridyl carboxylic acid, forexample,4-[4-(3,4-dichlorophenyl)phenylamino]-3-hydroxycarbonylpyridine.

[0177] Also provided is a method of inhibiting the aggregation ofanyloid proteins to form amyloid deposits, the method comprisingadministering to a patient in need of inhibition of the aggregation ofamyloid protein an amyloid protein aggregation inhibiting amount of acompound of Formula I

[0178] wherein

[0179] R^(a) is hydrogen, C₁-C₆ alkyl, or

[0180] n is 0 to 5 inclusive;

[0181] R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are independently hydrogen,halogen, —OH, —NH₂, NR^(b)R^(c), —CO₂H, —CO₂C₁-C₆ alkyl, —NO₂, —OC₁-C₁₂alkyl, —C₁-C₈ alkyl, —CF₃, —CN, —OCH₂ phenyl, —OCH₂-substituted phenyl,—(CH₂)_(m)-phenyl, —O-phenyl, —O-substituted phenyl, —CH═CH-phenyl,—O(CH₂)_(p)NR^(b)R^(c),

[0182]  —NH(CH₂)_(p)NR^(b)R^(c), —N(C₁-C₆alkyl)(CH₂)_(p)NR^(b)R^(c),

[0183] R⁸ is COOH, tetrazolyl, —SO₂R^(d), or —CONHSO₂R^(d);

[0184] R^(b) and R^(C) are independently hydrogen, —C₁-C₆ alkyl,—(CH₂)_(m)-phenyl, or R^(b) and R^(C) taken together with the nitrogenatom to which they are attached form a cyclic ring selected frompiperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C₁-C₆alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, orpyrazolyl;

[0185] R^(d) is hydrogen, —C₁-C₆ alkyl, —CF₃, or phenyl;

[0186] m is 0 to 5 inclusive;

[0187] p is 1 to 5 inclusive;

[0188] A is CH or N;

[0189] R¹ and R², when adjacent to one another, can be methylene-dioxy;

[0190] or the pharmaceutically acceptable salts thereof.

[0191] In a preferred embodiment of the method, in the compounds ofFormula I

[0192] R^(a) is hydrogen;

[0193] n is 2; and

[0194] R³ and R⁴ are hydrogen.

[0195] In a preferred embodiment of the method, in the compounds ofFormula I

[0196] R^(a) is hydrogen;

[0197] R³ and R⁴ are hydrogen; and

[0198] n is 2 to 5 inclusive.

[0199] In a preferred embodiment of the method, in the compounds ofFormula I

[0200] R^(a) is hydrogen;

[0201] n is 2;

[0202] R³ and R⁴ are hydrogen; and

[0203] R¹, R², and R⁷ are independently chlorine, —N(CH₂CH₃)₂, —OH,CH₃—, fluorine, —CF₃, phenyl, hydrogen, —OCH₂ phenyl, —O(CH₂)₃N(CH₃)₂,—O phenyl, —O(CH₂)₇CH₃, —CH(CH₂OCH₂CH₃)₂, pyrrolyl, —CH═CH-phenyl,

[0204]  —N[(CH₂)₃CH₃]₂, substituted phenyl, —OCH₂-substituted phenyl,pyrazolyl, or —N(phenyl)₂.

[0205] In a preferred embodiment of the method, in the compounds ofFormula I R^(a) is hydrogen;

[0206] n is 3, 4, or 5;

[0207] R³ and R⁴ are hydrogen; and

[0208] R¹, R², and R⁷ are independently chlorine or hydrogen.

[0209] In a preferred embodiment of the method, in the compounds ofFormula I

[0210] R^(a) is hydrogen;

[0211] n is 2;

[0212] R³ and R⁴ are hydrogen; and

[0213] R⁵ and R⁶ are independently hydrogen, —CO₂H, —NO₂, —OCH₃,imidazolyl, —CN, fluorine, —CH₃, —CF₃, halogen, —NH—C₁-C₆ alkyl,—N(C₁-C₆alkyl)₂, —NH₂, or pyrrolyl.

[0214] In a preferred embodiment of the method, in the compounds ofFormula I

[0215] R^(a) is hydrogen;

[0216] n is 2;

[0217] R³ and R⁴ are hydrogen; and

[0218] R⁵ is —CO₂H.

[0219] Also provided is a preferred method of inhibiting the aggregationof amyloid proteins to form amyloid deposits, the method comprisingadministering to a patient in need of inhibition of the aggregation ofamyloid protein an amyloid protein aggregation inhibiting amount of acompound of Formula I

[0220] wherein

[0221] R^(a) is hydrogen;

[0222] n is 1 to 5 inclusive;

[0223] R³ and R⁴ are hydrogen;

[0224] R¹, R⁷, and R² are independently chlorine, —N(CH₂CH₃)₂, —OH,CH₃—, fluorine, —CF₃, phenyl, hydrogen, —OCH₂ phenyl, —O(CH₂)₃N(CH₃)₂,—O phenyl, —O(CH₂)₇CH₃, —CH(CH₂OCH₂CH₃)₂, pyrrolyl, —CH═CH-phenyl,—N[(CH₂)₃CH₃]₂, substituted phenyl, —OCH₂-substituted phenyl, pyrazolyl,or —N(phenyl)₂;

[0225] R⁵ and R⁶ are independently hydrogen, —CO₂H, —NO₂, —OCH₃,imidazolyl, —CN, fluorine, —CH₃, —CF₃, or pyrrolyl;

[0226] R⁸ is COOH or tetrazolyl;

[0227] or the pharmaceutically acceptable salts thereof.

[0228] The most preferred compounds provided by the invention haveFormula II

[0229] and pharmaceutically acceptable salts thereof,

[0230] wherein:

[0231] R¹ is halo;

[0232] R² is H or halo; and

[0233] n and R⁶ are as defined above in Formula I.

[0234] Another preferred group of compounds have Formula III

[0235] and pharmaceutically acceptable salts thereof,

[0236] wherein:

[0237] R¹ is halo;

[0238] R² is H or halo; and

[0239] n and R⁶ are as defined above in Formula I.

[0240] Another group of preferred invention compounds have Formula IV

[0241] and pharmaceutically acceptable salts thereof,

[0242] wherein:

[0243] R¹ is halo;

[0244] R² is H or halo; and

[0245] n and R⁶ are as defined above in Formula I.

[0246] In a preferred embodiment of the method, the novel compounds ofFormula I are provided which are

[0247] 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid;

[0248] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid;

[0249]2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-4-methoxy-5-nitrobenzoicacid;

[0250] 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid;

[0251] 2-{4-[2-(4-Dibutyl amino-phenyl)-ethyl]phenylamino}benzoic acid;

[0252] 2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid;

[0253]2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}4-methoxy-5-nitrobenzoicacid;

[0254]2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}4-imidazo-1-yl-5-nitrobenzoicacid;

[0255] 2-{4-[2-[-(3,4-Dichlorophenyl)-propyl]phenylamino}benzoic acid;

[0256] 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid;

[0257] 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoicacid;

[0258]2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}-3,5-dinitrobenzoic acid;

[0259] 2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoicacid;

[0260]2-{4-[5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoicacid;

[0261] 2-[4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid;

[0262] 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid;

[0263] 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid;

[0264]2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0265] 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid;

[0266] 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid;

[0267] 2-(4-Phenethyl-phenylamino)-benzoic acid;

[0268]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoicacid;

[0269] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-terephthalicacid;

[0270]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid;

[0271] 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalicacid;

[0272]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methanesulfonyl-benzoicacid;

[0273]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-imidazol-1-yl-benzoicacid;

[0274] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro-benzoicacid;

[0275] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}4-nitro-benzoicacid;

[0276] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-nitro-benzoicacid;

[0277] 5-Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0278]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}4,6-difluoro-benzoicacid;

[0279]6-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-2,3-difluoro-benzoicacid;

[0280]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-fluoro-benzoic acid;

[0281]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-fluoro-benzoic acid;

[0282]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-methyl-benzoic acid;

[0283]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-fluoro-benzoic acid;

[0284]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3,5-difluoro-benzoicacid;

[0285]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-trifluoromethyl-benzoicacid;

[0286]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-trifluoromethyl-benzoicacid;

[0287]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid;

[0288]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-pyrrol-1-yl-benzoicacid;

[0289] 2-{4-[2-(4-Benzyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0290] 2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl]-ethyl}-phenylamino)-benzoic acid;

[0291] 2-{4-[2-(4-Diethylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0292] 2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0293] 2-{4-[2-(4-Octyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0294]2-(4-{2-[4-(2-Ethoxy-1-ethoxymethyl-ethyl)-phenyl]-ethyl)-phenylamino}-benzoicacid;

[0295] 2-{4-[2-(4-Pyrrol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0296] 2-{4-[2-(4-Styryl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0297] 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0298] 2-{4-[2-(4′-Ethyl-biphenyl-4-yl)-ethyl]-phenylamino}-benzoicacid;

[0299] 2-{4-[2-(4-Octyl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0300]2-(4-{2-[3-(3,5-Dichloro-phenoxy)-phenyl]-ethyl)-phenylamino}-benzoicacid;

[0301]2-(4-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0302] 2-{4-[2-(4-Pyrazol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0303] 2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0304]2-(4-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0305] 2-{4-[2-[(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoicacid;

[0306] 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid;

[0307]2-[[4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]phenyl]amino-benzoicacid; or

[0308] 2-[4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.

[0309] The present invention also provides the compounds:

[0310]2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-4-methoxy-5-nitrobenzoicacid;

[0311] 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid;

[0312] 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid;

[0313] 2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid;

[0314]2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoicacid;

[0315]2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoicacid;

[0316] 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid;

[0317] 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoicacid;

[0318]2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}-3,5-dinitrobenzoic acid;

[0319] 2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoicacid;

[0320]2-{4-[5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoicacid;

[0321] 2-[4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid;

[0322] 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid;

[0323] 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid;

[0324]2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0325] 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid;

[0326] 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid;

[0327] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-amino-benzoicacid;

[0328]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid;

[0329] 2-{4-[2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid;

[0330] 2-(4-Phenethyl-phenylamino)-benzoic acid;

[0331]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoicacid;

[0332] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-terephthalicacid;

[0333]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid;

[0334] 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalicacid;

[0335]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methanesulfonyl-benzoicacid;

[0336]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-imidazol-1-yl-benzoicacid;

[0337] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro-benzoicacid;

[0338] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-nitro-benzoicacid;

[0339] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-nitro-benzoicacid;

[0340] 5-Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0341]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}4,6-difluoro-benzoicacid;

[0342]6-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-2,3-difluoro-benzoicacid;

[0343]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-fluoro-benzoic acid;

[0344]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-fluoro-benzoic acid;

[0345]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-methyl-benzoic acid;

[0346]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-fluoro-benzoic acid;

[0347]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3,5-difluoro-benzoicacid;

[0348]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-trifluoromethyl-benzoicacid;

[0349]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-trifluoromethyl-benzoicacid;

[0350]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid;

[0351]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-pyrrol-1-yl-benzoicacid;

[0352] 2-{4-[2-(4-Benzyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0353]2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0354] 2-{4-[2-(4-Diethylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0355] 2-(4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino)-benzoic acid;

[0356] 2-{4-[2-(4-Octyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0357]2-(4-{2-[4-(2-Ethoxy-1-ethoxymethyl-ethyl)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0358] 2-{4-[2-(4-Pyrrol-1-yl-phenyl)-ethyl]-phenyl amino}-benzoic acid;

[0359] 2-{4-[2-(4-Styryl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0360] 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0361] 2-{4-[2-(4′-Ethyl-biphenyl-4-yl)-ethyl]-phenylamino}-benzoicacid;

[0362] 2-{4-[2-(4-Octyl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0363]2-(4-{2-[3-(3,5-Dichloro-phenoxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0364]2-(4-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0365] 2-{4-[2-(4-Pyrazol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;

[0366] 2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylamino}-benzoicacid;

[0367]2-(4-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;

[0368] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-amino-benzoicacid;

[0369] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid;

[0370] 2-{4-[2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid;

[0371] 2-{4-[2-[(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoicacid;

[0372] 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid;

[0373]2-{4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]phenylamino}-benzoicacid;

[0374] 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid;

[0375] 2-{4-[3-(4-Nitrophenyl)propyl]phenylwamino}benzoic acid;

[0376] 2-{4-[3-(3-Nitrophenyl)propyl]phenylamino}benzoic acid;

[0377] 2-{4-[3-(4-Aminophenyl)propyl]phenylamino}benzoic acid;

[0378] 2-{4-[3-(3-Aminophenyl)propyl]phenylamino}benzoic acid;

[0379] 2-{4-[2-(4-Aminophenyl)ethyl]phenylamino}benzoic acid;

[0380] 2-{4-[2-(4-Dipropylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0381] 2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride monohydrate;

[0382] 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenylamino}benzoic acid;

[0383] 2-{4-[3-(3-Dimethylaminophenyl)propyl]phenylamino}benzoic acid;

[0384] 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoic acid;

[0385]2-(N-{4-[3-(4-Diethylaminophenyl)propyl]phenyl)-N-ethylamino}benzoicacid;

[0386] 2-{4-[2-(3-Dibenzyl aminophenyl)ethyl]phenylamino}benzoic acid;

[0387] 2-{4-[3-(3-Diethylaminophenyl)propyl]phenylamino}benzoic acid;

[0388] 2-{4-[2-(3-Aminophenyl)ethyl]phenylamino}benzoic acid;

[0389] 2-{4-[3-(4-Dimethylaminophenyl)propyl]phenylamino}benzoic acid;

[0390] 2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino}benzoic acid;

[0391] 2-{4-[2-(3-Acetylaminophenyl)ethyl]phenylamino}benzoic acid;

[0392] 2-{4-[2-(3-Dipropylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0393] 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0394] 2-{4-[3-(4-Acetylaminophenyl)propyl]phenylamino}benzoic acid;

[0395] 2-{4-[3-(3-Acetyl aminophenyl)propyl]]phenylamino}benzoic acid;

[0396] 2-{4-[3-(3-Diethylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0397] 2-{4-[2-(3-Piperidin-1-ylphenyl)ethyl]phenylamino}benzoic acidmonohydrochloride;

[0398] 2-{4-[3-(4-Dipropylaminophenyl)propyl]phenylamino}benzoic acid;

[0399] 2-{4-[3-(4-Dibutylaminophenyl)propyl]phenylamino}benzoic acid;

[0400] 2-{4-[3-(3-Dibutylaminophenyl)propyl]phenylamino}benzoic acid;

[0401] 2-(4-{3-[4-(1H-Pyrrol-1-yl)phenyl]propyl}phenylamino) benzoicacid;

[0402] 2-{4-[3-(4-Piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid;

[0403] 2-{4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino}benzoicacid;

[0404] 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino}benzoic acid;

[0405] 2-{4-[3-(4-Diethylaminomethylphenyl)propyl]phenylamino}benzoicacid;

[0406] 2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino}benzoic acid;

[0407] 2-{4-[3-(3-Propylaminophenyl)propyl]phenylamino}benzoic acid;

[0408] 2-{4-[3-(4-Pyrrolidin-1-yl-phenyl)-propyl]-phenylamino}-benzoicacid;

[0409] 2-{4-[3-(3-Piperidin-1-yl-phenyl)-propyl]-phenylamino}-benzoicacid;

[0410]{5-[(1-Butyl-1,2,3,4-tetrahydro-6-quinolyl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}aceticacid;

[0411]{5-[(1-Butyl-2,3-dihydro-1H-indol-5-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}aceticacid;

[0412]3-{5-[(1-Butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoicacid;

[0413]4-{5-[(1-Butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}butanoicacid; or

[0414] 2-[4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.

[0415] Also provided are the foregoing compounds wherein the terminalphenylalkyl group is attached at the 2- or 3-position of the centralphenyl ring, i.e., compounds of the Formula Ia

[0416] Typical 2- and 3-substituted compounds are:

[0417] 2-{3-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid;

[0418] 2-{2-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid;

[0419] 2-{3-[3-(4-Diethylaminophenyl)propyl]phenylamino}-benzoic acid;

[0420] 2-{3-[3-(4-Di-n-propylaminophenyl)propyl]phenylamino}-benzoicacid;

[0421] 2-{3-[3-(4-n-Propylaminophenyl)propyl]phenylamino}-benzoic acid;

[0422]2-{3-[3-(4-[2-Diethylaminoethylamino]phenyl)propyl]phenylamino}-benzoicacid;

[0423]2-{2-[3-(4-[Hydroxycarbonylmethylamino]phenyl)propyl]phenylamino}-benzoicacid;

[0424] 2-{2-[2-(3-[2-Diethylaminoethylamino]phenyl)ethyl]phenylamino}-benzoic acid;

[0425] 2-{3-[3-(4-Morpholinophenyl)propyl]phenylamino}-benzoic acid;

[0426] 2-{3-[3-(4-piperazinylphenyl)propyl]phenylamino}-benzoic acid;

[0427] 2-{3-[2-(4-Chlorophenyl)ethyl]phenylamino}-benzoic acid;

[0428] 2-{3-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-benzoic acid; and

[0429] 2-{4-[4-(4-{4-Methylpiperazinyl}phenyl)butyl]phenylamino}-benzoicacid.

[0430] Pharmaceutical formulations of the novel compounds admixed with apharmaceutically acceptable diluent, carrier, or excipient are alsoprovided.

[0431] Also provided is a method of imaging amyloid deposits, the methodcomprising:

[0432] a. introducing into a patient a detectable quantity of a labeledcompound having the Formula I or a pharmaceutically acceptable saltthereof:

[0433]  wherein

[0434] R^(a) is hydrogen, C₁-C₆ alkyl, or

[0435] n is 0 to 5 inclusive;

[0436] R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are independently hydrogen,halogen, —OH, —NH₂, NR^(b)R^(c), —CO₂H, —CO₂C₁-C₆ alkyl, —NO₂, —OC₁-C₁₂alkyl, —C₁-C₈ alkyl, —CF₃, —CN, —OCH₂ phenyl, —OCH₂-substituted phenyl,—(CH₂)_(m)-phenyl, —O-phenyl, —O-substituted phenyl, —CH═CH-phenyl,—O(CH₂)_(p)NR^(b)R^(c),

[0437]  —NH(CH₂)_(p)NR^(b)R^(c), —N(C₁-C₆alkyl)(CH₂)_(p)NR^(b)R^(c),

[0438] R⁸ is COOH, tetrazolyl, —SO₂R^(d), or —CONHSO₂R^(d);

[0439] R^(b) and R^(C) are independently hydrogen, —C₁-C₆ alkyl,—(CH₂)_(m)-phenyl, or R^(b) and R^(c) taken together with the nitrogenatom to which they are attached form a cyclic ring selected frompiperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C₁-C₆alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, orpyrazolyl;

[0440] R^(d) is hydrogen, —C₁-C₆ alkyl, —CF₃, or phenyl;

[0441] m is 0 to 5 inclusive;

[0442] p is 1 to 5 inclusive;

[0443] A is CH or N;

[0444] R¹ and R², when adjacent to one another, can be methylene-dioxy;

[0445] or the pharmaceutically acceptable salts thereof;

[0446] b. allowing sufficient time for the labeled compound to becomeassociated with amyloid deposits; and

[0447] c. detecting the labeled compound associated with the amyloiddeposits.

[0448] In a preferred embodiment of the method, the patient has or issuspected to have Alzheimer's disease.

[0449] In a preferred embodiment of the method, the labeled compound isa radio labeled compound.

[0450] In a preferred embodiment of the method, the labeled compound isdetected using MRI.

[0451] The present invention also provides the preferred compounds:

[0452] 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid;

[0453] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid;

[0454] 2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino}benzoic acid;

[0455]2-[[4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]phenyl]amino-benzoicacid;

[0456] 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}-benzoic acid;

[0457] and pharmaceutical formulations thereof.

[0458] Pharmaceutically acceptable acid addition salts, amides, andprodrugs of the foregoing compounds are also provided by this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0459] The term “alkyl” means a straight or branched chain hydrocarbonhaving from 1 to 12 carbon atoms. Representative examples of alkylgroups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl,tert-butyl, sec-butyl, pentyl, hexyl, octyl, decyl, and1,1-dimethyloctyl.

[0460] Preferred alkyl groups are C₁-C₈ alkyl, and especially C₁-C₆alkyl.

[0461] The term “alkoxy” means an alkyl group attached to an oxygenatom. Representative examples of alkoxy groups include methoxy, ethoxy,tert-butoxy, propoxy, and isobutoxy. Preferred alkoxy groups are C₁-C₁₋₂alkoxy, and especially C₁-C₆ alkoxy.

[0462] The term “halogen” includes chlorine, fluorine, bromine, andiodine.

[0463] The term “substituted” means that one or more hydrogen atom in amolecule has been replaced with another atom or group of atoms. Forexample, substituents include halogen, especially chloro, —OH, —CF₃,—NO₂, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, C₁-C₆ alkyl, —OC₁-C₆alkyl, —CN, —CF₃, —CO₂H, and —CO₂C₁-C₆ alkyl.

[0464] The term “substituted phenyl” means a phenyl ring in which from 1to 4 hydrogen atoms have been independently replaced with a substituent,preferably one selected from the list above. Typical “substitutedphenyl” groups include 4-chlorophenyl, 3,4-dibromophenyl,3-fluoro-4-methylphenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl,and 4-dimethylaminophenyl.

[0465] The symbol “—” means a covalent bond.

[0466] Substituent groups represented by R¹, R³, and R⁵, for example,include amino(NR^(b)R^(c)) and acylamino (—NHCOR^(b)). R^(b) and R^(c)can be hydrogen, alkyl and phenylalkyl and substituted phenylalkyl, andtypical NR^(b)R^(c) groups include methylamino, diethylamino,isobutyl-propylamino, benzylamino, and 3,4-dimethoxybenzylamino.Examples of acylamino groups include formamido, acetamido,2-phenylacetamido, and 2-(3-nitrophenyl)acetamido. R¹, R³, and R⁵ canalso be aminoalkoxy (—O(CH₂)_(p)NR^(b)R^(c)) such asN-methylaminomethoxy and 2-(N-benzylamino)ethoxy, as well asaminoalkylamino (—NH(CH₂)_(p)NR^(b)R^(c)) such as3-(dimethylamino)propylamino and 2-(N-ethyl-N-benzylamino)ethylamino.Substituent groups such as R¹, R³, and R⁵ additionally can be cyclicstructures, for instance when NR^(b)R^(C) is part of the substituentgroup, and R^(b) and R^(c) are taken together with the nitrogen to whichthey are attached to form a cyclic ring selected from imidazole,pyrrole, piperidine, piperazine, 4-C₁-C₆ alkylpiperazine, morpholine,thiomorpholine, pyrazole, and decahydroisoquinoline.

[0467] Substituent groups such as R¹, R², R⁵, R⁶, and R⁷ also can be—CH═CH-phenyl (i.e., styryl), phenoxy, O-substituted phenyl such as3-iodophenoxy, 2,4,6-trihydroxyphenoxy, 2-fluoro-3-nitrophenoxy, as wellas —O-benzyl and —O-substituted benzyl such as2-trifluoromethylbenzyloxy and 4-aminobenzyloxy.

[0468] The term “pharmaceutically acceptable salt, ester, amide, andprodrug” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medicaljudgement, suitable for use in contact with the tissues of patientswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “salts” refers to therelatively nontoxic, inorganic and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laureate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate,glucoheptonate, lactobionate and laurylsulphonate salts, and the like.These may include cations based on the alkali and alkaline earth metals,such as sodium, lithium, potassium, calcium, magnesium, and the like, aswell as, nontoxic ammonium, quaternary ammonium and amine cationsincluding, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like. (See, for example, Berge S. M.,et al., Pharmaceutical Salts, J. Pharm. Sci, 66:1-19 (1977) which isincorporated herein by reference.)

[0469] Examples of pharmaceutically acceptable, nontoxic esters of thecompounds of this invention include C₁-C₆ alkyl esters wherein the alkylgroup is a straight or branched chain. Acceptable esters also includeC₅-C₇ cycloalkyl esters as well as arylalkyl esters such as, but notlimited to benzyl. C₁-C₄ alkyl esters are preferred. Esters of thecompounds of the present invention may be prepared according toconventional methods, for example by reacting a carboxylic acid ofFormula I with an alcohol such as ethanol or benzyl alcohol.

[0470] Examples of pharmaceutically acceptable, nontoxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁-C₆ alkyl amines and secondary C I—C₆ dialkyl amines wherein the alkylgroups are straight or branched chain. In the case of secondary amines,the amine may also be in the form of a 5- or 6-membered heterocyclecontaining one nitrogen atom. Amides derived from ammonia, C I—C₃ alkylprimary amides and C₁-C₂ dialkyl secondary amides are preferred. Amidesof the compounds of the invention may be prepared according toconventional methods.

[0471] The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formulas,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein byreference.

[0472] In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

[0473] The compounds of the present invention can exist in differentstereoisometric forms by virtue of the presence of asymmetric centers inthe compounds. It is contemplated that all stereoisometric forms of thecompounds, as well as mixture thereof, including racemic mixtures, formpart of this invention.

[0474] In the first step of the present method of imaging, a labeledcompound of Formula I is introduced into a tissue or a patient in adetectable quantity. The compound is typically part of a pharmaceuticalcomposition and is administered to the tissue or the patient by methodswell-known to those skilled in the art.

[0475] In the methods of the present invention, a compound can beadministered either orally, rectally, parenterally (intravenous, byintramuscularly or subcutaneously), intracistemally, intravaginally,intraperitoneally, intravesically, locally (powders, ointments ordrops), or as a buccal or nasal spray.

[0476] Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

[0477] These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antiflngalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

[0478] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound is admixed with at least one inert customary excipient(or carrier) such as sodium citrate or dicalcium phosphate or (a)fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates andsodium carbonate; (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

[0479] Solid compositions of a similar type may also be employed asfillers in soft- and hard-filled gelatin capsules using such excipientsas lactose or milk sugar, as well as high molecular weightpolyethyleneglycols, and the like.

[0480] Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicroencapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

[0481] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs. In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art, such as wateror other solvents, solubilizing agents and emulsifiers, as for example,ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil, and sesame oil, glycerol,tetrahydrofurfaryl alcohol, polyethyleneglycols, and fatty acid estersof sorbitan or mixtures of these substances, and the like.

[0482] Besides such inert diluents, the composition can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

[0483] Suspensions, in addition to the active compounds, may containsuspending agents, as for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances, and the like.

[0484] Compositions for rectal administrations are preferablysuppositories which can be prepared by mixing the compounds of thepresent invention with suitable nonirritating excipients or carrierssuch as cocoa butter, polyethyleneglycol or a suppository wax, which aresolid at ordinary temperatures but liquid at body temperature andtherefore, melt in the rectum or vaginal cavity and release the activecomponent.

[0485] Dosage forms for topical administration of a compound of thisinvention include ointments, powders, sprays, and inhalants. The activecomponent is admixed under sterile conditions with a physiologicallyacceptable carrier and any preservatives, buffers or propellants as maybe required. Ophthalmic formulations, eye ointments, powders, andsolutions are also contemplated as being within the scope of thisinvention.

[0486] In a preferred embodiment of the invention, the labeled compoundis introduced into a patient in a detectable quantity and aftersufficient time has passed for the compound to become associated withamyloid deposits, the labeled compound is detected noninvasively insidethe patient. In another embodiment of the invention, a labeled compoundof Formula I is introduced into a patient, sufficient time is allowedfor the compound to become associated with amyloid deposits, and then asample of tissue from the patient is removed and the labeled compound inthe tissue is detected apart from the patient. In a third embodiment ofthe invention, a tissue sample is removed from a patient and a labeledcompound of Formula I is introduced into the tissue sample. After asufficient amount of time for the compound to become bound to amyloiddeposits, the compound is detected.

[0487] The administration of the labeled compound to a patient can be bya general or local administration route. For example, the labeledcompound may be administered to the patient such that it is deliveredthroughout the body. Alternatively, the labeled compound can beadministered to a specific organ or tissue of interest. For example, itis desirable to locate and quantitate amyloid deposits in the brain inorder to diagnose or track the progress of Alzheimer's disease in apatient.

[0488] The term “tissue” means a part of a patient's body. Examples oftissues include the brain, heart, liver, blood vessels, and arteries. Adetectable quantity is a quantity of labeled compound necessary to bedetected by the detection method chosen. The amount of a labeledcompound to be introduced into a patient in order to provide fordetection can readily be determined by those skilled in the art. Forexample, increasing amounts of the labeled compound can be given to apatient until the compound is detected by the detection method ofchoice. A label is introduced into the compounds to provide fordetection of the compounds.

[0489] The term “patient” means humans and other animals. Those skilledin the art are also familiar with determining the amount of timesufficient for a compound to become associated with amyloid deposits.The amount of time necessary can easily be determined by introducing adetectable amount of a labeled compound of Formula I into a patient andthen detecting the labeled compound at various times afteradministration.

[0490] The term “associated” means a chemical interaction between thelabeled compound and the amyloid deposit. Examples of associationsinclude covalent bonds, ionic bonds, hydrophilic-hydrophilicinteractions, hydrophobic-hydrophobic interactions, and complexes.

[0491] Those skilled in the art are familiar with the various ways todetect labeled compounds. For example, magnetic resonance imaging (MRI),positron emission tomography (PET), or single photon emission computedtomography (SPECT) can be used to detect radiolabeled compounds. Thelabel that is introduced into the compound will depend on the detectionmethod desired. For example, if PET is selected as a detection method,the compound must possess a positron-emitting atom, such as ¹¹C or ¹⁸F.

[0492] Another example of a suitable label in a compound of Formula I isan atom such as ¹³C, ¹⁵N, or ¹⁹F which can be detected using magneticresonance imaging (MRI), which is also sometimes called nuclear magneticresonance (NMR). In addition, the labeled compounds of Formula I mayalso be detected by MRI using paramagnetic contrast agents.

[0493] Another example of detection is electron paramagnetic resonance(EPR). In this case, EPR probes which are well-known in the art, such asnitroxides, can be used.

[0494] The imaging of amyloid deposits can also be carried outquantitatively so that the amount of amyloid deposits can be determined.

[0495] The present invention also provides a method of inhibiting theaggregation of amyloid proteins to form amyloid deposits, byadministering to a patient in need of inhibition of the aggregation ofamyloid protein an amyloid protein inhibiting amount of a compound ofFormula I. Those skilled in the art are readily able to determine anamyloid inhibiting amount by simply administering a compound of FormulaI to a patient in increasing amounts until the growth of amyloiddeposits is decreased or stopped. The rate of growth can be assessedusing imaging or by taking a tissue sample from a patient and observingthe amyloid deposits therein.

[0496] A patient in need of inhibition of the aggregation of amyloidproteins is a patient having a disease or condition in which amyloidproteins aggregate. Examples of such diseases and conditions includeMediterranean fever, Muckle-Wells syndrome, idiopathetic myeloma,amyloid polyneuropathy, amyloid cardiomyopathy, systemic senileamyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage withamyloidosis, Alzheimer's disease, Down's syndrome, Scrapie,Creutzfeldt-Jacob disease, Kuru, Gerstmann-Straussler-Scheinkersyndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid,β₂-microglobulin amyloid in dialysis patients, inclusion body myositis,β₂-amyloid deposits in muscle wasting disease, and Islets of Langerhansdiabetes Type II insulinoma.

[0497] Also provided by the present invention are compounds of Formula Iwherein one or more atom in the compound has been replaced with aradioisotope (a labeled compound). The radioisotope can be anyradioisotope. However, 3H, ¹²³I, ¹²⁵I, ¹³¹I, ¹¹C, and ¹⁸F are preferred.Those skilled in the art are familiar with the procedure used tointroduce a radioisotope into a compound. For example, a compound ofFormula I wherein one carbon atom is ¹¹C or ¹⁴C is readily prepared.

[0498] The compounds of the present invention can be administered to apatient at dosage levels in the range of about 0.1 to about 1,000 mg perday. For a normal human adult having a body weight of about 70 kg, adosage in the range of about 0.01 to about 100 mg per kilogram of bodyweight per day is sufficient. The specific dosage used, however, canvary. For example, the dosage can depend on a number of factorsincluding the requirements of the patient, the severity of the conditionbeing treated, and the pharmacological activity of the compound beingused. The determination of optimum dosages for a particular patient iswell-known to those skilled in the art.

[0499] The examples presented below are intended to illustrateparticular embodiments of the invention and are not intended to limitthe scope of the specification, including the claims, in any manner.

EXAMPLES

[0500] Synthesis

[0501] Compounds of Formula I can be prepared by several routes asillustrated in Schemes 6 through 9. Schemes 1 through 5 show syntheticroutes that can be used to obtain the desired starting amines (IV),(VII), (XV), and (XXI).

[0502] In Scheme 1, the appropriately substituted aldehyde (I) and anitrophenylacetic acid (II) yield olefin (III) when heated in piperidineat 150° C. Standard hydrogenation conditions, such as Raney nickel, givedesired amine (IV).

[0503] Scheme 2 depicts the synthesis of amine (VIII) which contains athree methylene tether. Condensation of aldehyde (1) and nitro-ketone(V) in the presence of sodium hydroxide gives the desired alpha,beta-unsaturated ketone, which upon standard hydrogenation conditions(Raney nickel) gives (VII) and then Wolff-Kishner conditions yields thedesired amine (VIII).

[0504] Scheme 3 is very similar to Scheme 2, except that the aldehyde(I) is condensed with a substituted aniline (IX).

[0505] Scheme 4 illustrates standard Wittig conditions in which thestarting materials (XII) and (XIII) are obtained via aldol condensationand ylide chemistry, respectively. Reaction of aldehyde (XII) andbromophosphorane (XIII) in the presence of a base, such as butyllithium, gives diene (XIV). Standard reduction conditions (e.g., Raneynickel) of (XIV) yields the desired amine (XV).

[0506] Scheme 5 illustrates the synthesis of amine (XXI) which containsa 5-methylene tether. Wittig reaction of the bromophosporane (XVII),which is formed from the corresponding substituted bromide (XVI), andnitro aldehyde (XIX), obtained from Swern oxidation of the correspondingalcohol (XVIII), using a base (e.g., LHDMS) yields olefin (XX).Reduction of (XX) using standard conditions (Raney nickel) gives amine(XXI).

[0507] Scheme 6 illustrates one route to obtain compounds of Formula 1.Either by Buchwald coupling (Method A) followed by saponification orutilizing the Ullman reaction (Method B), compounds of Formula I can beisolated from amines such as (IV), (VIII), and (XV). Compounds ofFormula I that contain hydroxy groups, such as Examples 4 and 6, requiredemethylation of the hydroxy protecting groups with reagents such asboron tribromide in the final step of the synthesis.

[0508] Protecting groups will also be used when reactive functionalgroups such as amino and carboxylic acids are present, so as to avoidunwanted side reactions. Carboxy groups typically are converted toesters (e.g., tert-butyl, benzyl), and amino groups generally areacylated (e.g., acetyl or trimethylsilyl). These and other suchprotecting groups are well-known to organic chemists, and are fullydescribed by Greene and Wuts in Protective Groups in Organic Synthesis,John Wiley and Sons, New York (2^(nd) Ed. 1991). All citations areincorporated herein by reference.

[0509] Scheme 7 illustrates the synthesis of compounds of Formula I byreacting amines such as (IV), (VIII), and (XXI) with fluoro-nitrointermediate (XXIV), in the presence of a base (e.g., LHMDS or Et₃N) togive ester (XXV). This ester can then be saponified using standardconditions, such as sodium hydroxide.

[0510] In Scheme 8, amine (XV) can be coupled with readily availablefluoro-substituted carboxylic acids [e.g., (XXVI) or (XXVII)] in thepresence of various bases (such as DBU or triethylamine) to yieldcompounds of Formula 1.

[0511] Scheme 9 depicts coupling of amine (VIII) with readily availablemethyl ester (XXVIII) in the presence of a base, such as imidazole, togive ester (XXXI).

[0512] This ester can then be saponified as usual to give compounds ofFormula I.

[0513] Scheme 10 illustrates the synthesis of fluoro-intermediate (XXIV)which is obtained by nitration of readily available methyl ester (XXX)to give (XXVIII). Treatment of (X)CVIII) with potassium cyanide gives(XXIV).

[0514] In Scheme 11, the synthesis of compounds related to Example 18 isillustrated. Reaction of the potassium salts of ortho-substitutedbenzoic acids (XXVI) with substituted anilines (XXVII) in the presenceof potassium carbonate and cupric acetate yields variousiodo-substituted aminobenzoic acids (XXVIII). Reaction of (XXVIII) withsubstituted boronic acids and palladium chloride gives the desiredsubstituted aminobenzoic acids (XXX).

[0515] It should, of course, be recognized that several inventioncompounds of Formula I can be prepared from other compounds defined byFormula 1, utilizing standard organic reactions such as oxidation,reduction, alkylation, condensation, elimination, and similar well-knownsynthetic processes. For example, compounds of Formula I wherein R^(a)is hydrogen are readily alkylated to form compounds wherein R^(a) isC₁-C₆ alkyl. Compounds wherein R¹ is NH₂ are readily acylated byreaction with an acid halide or acid anhydride to provide compoundswherein R¹ is —NHCOR^(b). Similarly, compounds wherein R¹ is NO₂ areeasily reduced to provide compounds wherein R¹ is NH₂. The benzoic acids(where R⁸ is COOH) are readily converted to esters and amides, as wellas salts and other prodrugs by routine processes. For example, thebenzoic acid can be reacted with oxalylchloride to form the acidchloride, which then readily reacts with a sulfonamide such asmethanesulfonamide to produce the corresponding invention compound whereR⁸ is —CONHSO₂CH₃.

[0516] Formation of Amines

[0517] Coupling Routes

[0518] R is an ester forming group such as alkyl or benzyl.

[0519] Synthesis of Fluoro-Intermediate

Scheme 10

[0520]

Example 1

[0521] Preparation of2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid

[0522] Step A (Scheme 1): Preparation of1,2-Dichloro-4-[2-(4-nitrophenyl)ethenyl]-benzene

[0523] A mixture of p-nitrophenylacetic acid (51.23 g, 0.28 mol) and3,4-dichlorobenzaldehyde (49.50 g, 0.28 mol) in piperidine (50 mL) washeated to 150-160° C. for 5 hours under a N₂ atmosphere. After coolingthe reaction mixture, the precipitate was triturated in boiling methanol(MeOH) (50 mL) and then cooled to −5° C. for 12 hours. The crystallineprecipitate was filtered off, rinsed with cold MeOH and dried at roomtemperature in a vacuum oven overnight to yield an orange solid, 22.71 g(0.077 mol, 27%) of the desired product.

[0524] mp 190-191° C.

[0525] MS: 294.9 (M⁺).

[0526] Step B (Scheme 1): Preparation of4-[2-(3,4-Dichlorophenyl)ethyl]benzenamine

[0527] A sample of 1,2-dichloro-4-[2-(4-nitrophenyl)ethenyl]benzene(98.0 g, 0.33 mol) in tetrahydrofuran (THF) (1.6 L) was reduced in thepresence of Raney Nickel (Ra-Ni) (20 g) at 25° C. to 40° C. (ΔP=13.5psi) under a hydrogen atmosphere. The reaction mixture was filtered, andthe filtrate was concentrated in vacuo to give an orange solid, 85.0 g(0.32 mol, 95.8%) of the desired product. mp 68-70° C.

[0528] MS: 266.1 (M⁺).

[0529] Step C (Scheme 6): Preparation of2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid

[0530] Method A

[0531] A mixture of 4-[2-(3,4-dichlorophenyl)ethyl]benzenamine (28.37 g,106.59 mmol), methyl 2-bromobenzoate (19.10 g, 88.82 mmol), cesiumcarbonate (40.52 g, 124.35 mmol),tris(dibenzylideneacetone-dipaladium(0) (2.44 g, 2.67 mmol) and(S)-(2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%, (S)-tol-BINAP)(2.71 g, 4.00 mmol) (Ligand/Pd=1.5) in anhydrous toluene (300 mL) washeated to 100° C. for 34 hours under N₂. After cooling to roomtemperature, the reaction mixture was diluted with ether, filteredthrough celite and rinsed thoroughly with ether. The filtrate wasevaporated to dryness to give a brown residue (68 g). The resultedresidue was dissolved in ethanol (EtOH) (50 mL) and THF (100 mL), andthen 5N NaOH (aq.) (200 mL) was added, and the mixture was refluxed for16 hours. The solvent was removed in vacuum. The residue was acidifiedwith concentrated HCl to pH 3. The resulting precipitate was collectedby filtration, triturated with boiling MeOH—H₂O (4:1) and dried in avacuum at room temperature for 16 hours to give Example 1, an orangesolid (31.95 g, 0.083 mol, 77.6%). mp 175.0-177.0° C.

[0532] Analysis for C₂₁H₁₇N₁O₂Cl₂: Calcd: C, 65.30; H, 4.44; N, 3.63.Found: C, 65.40; H, 4.54; N, 3.50.

[0533] Method B

[0534] A mixture of 2-chlorobenzoic acid (5.4 g, 0.034 mol),4-[2-(3,4-dichlorophenyl)ethyl]benzenamine (10.0 g, 0.037 mol),anhydrous potassium carbonate (16.9 g, 0.12 mol), copper powder (4.94 g,0.077 mol), and copper(I) chloride (0.37 g, 0.0037 mol) in drydimethylformamide (DMF) (85 ML) was heated to reflux for 24 hours at150° C. The reaction mixture was poured into hot H₂O (150 mL) and heatedto 90° C. on a hot plate. Charcoal was added, and this mixture wasstirred at 90° C. for 5 minutes. The warm brown mixture was filteredthrough filter paper. The cooled filtrate was then acidified withconcentrated HCl (pH 1), and the precipitate was collected byfiltration, triturated with boiling MeOH—H₂O (1:2) and dried undervacuum at room temperature for 16 hours to give Example 1, an orangesolid (2.3 g, 0.006 mol, 17.5%). mp 165.0-173.0° C.

[0535] Analysis for C₂₁H₁₇N₁O₂Cl₂: Calcd: C, 65.30; H, 4.44; N, 3.63.Found: C, 65.68; H, 4.58; N, 3.60.

Example 2

[0536] Preparation of2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid

[0537] Step C (Scheme 6): Preparation of2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acidmethyl ester

[0538] A mixture of 4-[2-(3,4-dichlorophenyl)ethyl]benzenamine (600 mg,2.25 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (489 mg, 1.88mmol), cesium carbonate (857 mg, 2.62 mmol),tris(dibenzylideneacetone-dipaladium(O) (51 mg, 0.056 mmol) and(S)-(2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%, (S)-tol-BINAP)(58 mg, 0.085 mmol) (Ligand/Pd=1.5) in anhydrous toluene (16 mL) washeated to 100° C. for 12 hours under N₂. After cooling, the reactionmixture was diluted with ether, filtered through celite and rinsedthoroughly with ether. The filtrate was evaporated to dryness to give abrown residue. Purification by flash chromatography (silica gel, 5%EtOAc/hexane) yielded 540 mg (1.21 mmol, 64%) of the desired product. mp107-108° C.

[0539] Analysis for C₂₂H₁₈N₂Cl₂O₄: Calcd: C, 59.34; H, 4.07; N, 6.29.Found: C, 59.03; H, 4.04; N, 5.99.

[0540] Preparation of2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid

[0541] A solution of2-{4-[2-(3,4-dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acidmethyl ester (340 mg, 0.76 mmol) and 1N NaOH (aq.) (4.0 mL) in EtOH (4.0mL) and THF (4.0 mL) was heated to reflux for 16 hours. The solvent wasremoved in vacuum. The residue was diluted with H₂O and acidified withconcentrated HCl to pH 1. The mixture was then extracted with methylenechloride, dried (Na₂SO₄), filtered and concentrated in vacuo to yield ayellow solid, 329 mg (0.76 mmol, 100%) of the desired product. mp214-217° C.

[0542] Analysis for C₂₁H₁₆N₂Cl₂O₄: Calcd: C, 58.49; H, 3.74; N, 6.50.Found: C, 58.24; H, 3.81; N, 6.28.

Example 3

[0543] Preparation of2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-4-methoxy-5-nitrobenzoicacid

[0544] To a cooled (−78° C.) solution of4-[2-(3,4-dichloro-phenyl)-ethyl]phenylamine (0.836 g, 3.14 mmol) in THF(20 mL), LHDMS (6.28 mL, 1 M in THF, 6.28 mmol) was added dropwise. Thereaction mixture was allowed to stir at −78° C. for 10 minutes. Asolution of 2-flouro-4-methoxy-5-nitrobenzoic acid methyl ester (0.72 g,3.14 mmol) in THF (30 mL) was added dropwise, and this solution wasstirred for 30 minutes at −78° C. The reaction mixture was allowed togradually warm to room temperature and stir for 2 hours under a N₂atmosphere. The reaction mixture was diluted with ethyl acetate (EtOAc),and acidified with 5N HCl (pH 3). The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo to yield a brown residue. To asolution of this residue in EtOH (20 mL) and THF (40 mL), 5N NaOH (50mL) was added, and the mixture was refluxed for overnight. The solventwas removed in vacuum, and the residue was acidified with concentratedHCl (pH 3). The precipitate was collected by filtration, triturated withboiling MeOH—H₂O (1:1), and dried in a vacuum oven for 16 hours to giveExample 3, an orange solid (0.70 g, 1.51 mmol, 48%). mp 208-209° C.

[0545] Analysis for C₂₂H₁₈N₂O₅Cl₂: Calcd: C, 57.28; H, 3.93; N, 6.07.Found: C, 57.43; H, 3.69; N, 5.86.

Example 4

[0546] Preparation of2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid

[0547] Step A (Scheme 1): Preparation of1,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]-benzene

[0548] The title compound was prepared from p-nitrophenylacetic acid(25.0 g, 0.14 mol), and 3,4-dimethoxybenzaldehyde (21.0 g, 0.14 mol) inpiperidine (5 mL) using the procedure described in Example 1, Step A, toyield a yellow solid, 13.4 g (0.047 mol, 34%) of the desired product.mp: 133-134° C.

[0549] Analysis of C₁₆H₁₅N₁O₄: Calcd: C, 67.36; H, 5.30; N, 4.91. Found:C, 66.81; H, 5.27; N, 4.84.

[0550] Step B (Scheme 1): Preparation of4-[2-(3,4-Dimethoxy-phenyl)ethyl]-phenylamine

[0551] 1,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]benzene (12.1 g, 0.042mol) was reduced in the presence of 10% Pd—C (2.0 g) indimethylformamide (DMF) (120 mL) at 25° C. under a hydrogen atmosphere.The reaction mixture was concentrated in vacuo to give a solid. Thesolid was recrystallized from MeOH (400 mL) to yield a white crystallineproduct, 6.8 g (0.026 mol, 63%) of the desired product. mp 115-116° C.

[0552] Analysis for C₁₆H₁₉N₁O₂: Calcd: C, 74.68; H, 7.44; N, 5.44.Found: C, 74.60; H, 7.39; N, 5.35.

[0553] Step C (Scheme 6): Preparation of2-{4-[2-(3,4-Dimethoxy-phenyl)ethyl]-phenylamino}benzoic acid

[0554] The title compound was prepared from4-[2-(3,4-dimethoxy-phenyl)-ethyl]phenylamine (9.25 g, 0.036 mol),2-chlorobenzoic acid (5.2 g, 0.036 mol), anhydrous potassium carbonate(15.0 g, 0.11 mol), copper powder (0.45 g, 0.007 mol), and a catalyticamount of copper(I) chloride in dry DMF (75 mL) using the proceduredescribed in Example 1, Step C, Method B. After crystallization withMeOH/H₂O, 4.5 g (0.012 mol, 33%) of the desired product was obtained.mp: 137-139° C.

[0555] Analysis for C₂₃H₂₃N₁O₄: Calcd: C, 73.19; H, 6.14; N, 3.71.Found: C, 73.47; H, 6.03; N, 3.78.

[0556] Step D: Preparation of2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}-benzoic acid

[0557] To a solution of2-{4-[2-(3,4-dimethoxy-phenyl)-ethyl]phenylamino}-benzoic acid (0.28 g,0.74 mmol) in CH₂Cl₂ (20 mL), BBr₃ (3.5 mL, 1 M in CH₂Cl₂, 3.5 mmol) wasadded at room temperature under a N₂ atmosphere. The reaction mixturewas allowed to stir at room temperature for 2 hours and then poured intoice water (50 mL). This mixture was extracted with EtOAc, and theorganic layer was washed two times with water, dried (Na₂SO₄), filteredand concentrated in vacuo to yield 0.24 g (0.69 mmol, 93%) of thedesired product. mp 215-217° C.

[0558] Analysis for C₂₁H₁₉NO₄: Calcd: C, 72.19; H, 5.48; N, 4.00. Found:C, 71.80; H, 5.46; N, 3.99.

Example 5

[0559] Preparation of2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid

[0560] Step A (Scheme 1): Preparation of1,1-Dibutylamino-4-[2-(4-nitrophenyl)ethenyl]benzene

[0561] The title compound was prepared from p-nitrophenylacetic acid(9.92 g, 0.055 mol) and 4-dibutylamino-benzaldehyde (14.32 g, 0.055 mol)in piperidine (5 mL) using the procedure described in Example 1, Step A.This procedure yielded a red solid, 4.12 g (0.012 mol, 16%) of thedesired product.

[0562] MS: 352.2. (M⁺); 353.2. (MH⁺).

[0563] Step B (Scheme 1): Preparation of4-[2-(4,4-Dibutylaminophenyl)ethyl]-phenylamine

[0564] The title compound was prepared from1,1-dibutylamino-4-[2-(4-nitrophenyl)ethenyl]benzene (4.10 g, 11.63mmol) and Ra-Ni (2.0 g) in MeOH (100 mL) at 21° C. to 32° C. (ΔP=3.6psi) under a hydrogen atmosphere using the procedure described inExample 1, Step B. This procedure yielded a colorless oil, 3.49 g (10.76mmol, 92.6%) of the desired product.

[0565] MS: 325.3 (MH⁺).

[0566] Step C (Scheme 6): Preparation of2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}-benzoic acid

[0567] The title compound was prepared from 2-chlorobenzoic acid (1.46g, 9.36 mmol), 4-[2-(4,4-dibutylaminophenyl)ethyl]phenylamine (3.31 g,10.20 mmol), anhydrous potassium carbonate (4.27 g, 30.88 mmol), copperpowder (1.25 g, 19.65 mmol), and copper(I) chloride (0.092 g, 0.93 mmol)in dry DMF (30 mL) using the procedure described in Example 1, Step C,Method B. This procedure yielded a 0.39 g (0.87 nmol, 8.6%) of thedesired product.

[0568] mp 115-117° C.

[0569] Analysis for C₂₉H₃₆N₂O₂: Calcd: C, 78.34; H, 8.16; N, 6.30.Found: C, 78.15; H, 8.07; N, 6.10.

Example 6

[0570] Preparation of2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid

[0571] Step A (Scheme 1): Preparation of1,2,3-Trimethoxy-5-[2-(4-nitrophenyl)ethenyl]benzene

[0572] The title compound was prepared from p-nitrophenylacetic acid(18.6 g, 0.10 mol), 3,4,5-trimethoxy-benzaldehyde (19.6 g, 0.10 mol) andpiperidine (5 mL) using the procedure described in Example 1, Step A.This procedure yielded a solid, 13.0 g (0.041 mol, 41%) of the desiredproduct. mp: 192-195° C.

[0573] Step B (Scheme 1): Preparation of4-[2-(3,4,5-Trimethoxy-phenyl)ethyl]-phenylamine

[0574] The title compound was prepared from1,2,3-trimethoxy-5-[2-(4-nitrophenyl)ethenyl]benzene (9.5 g, 0.03 mol)and Ra-Ni (1.0 g) in THF (50 mL) at 21-26° C. (ΔP=9.6 psi) under ahydrogen atmosphere using the procedure described in Example 1, Step B.This procedure yielded a tan powder, 6.6 g (0.023 mol, 74%) of thedesired product. mp 91-93° C.

[0575] Step C (Scheme 6): Preparation of2-{4-[2-(3,4,5-Trimethoxy-phenyl)-ethyl]phenylamino}-benzoic acid methylester

[0576] The title compound was prepared from4-[2-(3,4,5-trmethoxyphenyl)-ethyl]phenylamine (0.75 g, 2.61 mmol),methyl 2-bromobenzoate (0.47 g, 2.17 mmol), cesium carbonate (0.99 g,3.04 mmol), tris(dibenzylideneacetone-dipaladium(0) (0.06 g, 0.065 mmol)and (S)-(—O—2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%(S)-Tol-BINAP) (0.066 g, 0.098 mmol) (Ligand/Pd=1.5) in anhydroustoluene (100 mL) using the procedure described in Example 1, Step C,Method A to yield a yellow oil, 0.69 g (1.63 mmol, 76%) of the desiredproduct.

[0577] Analysis for C₂₅H₂₇N₁O₅: Calcd: C, 71.24; H, 6.46; N, 3.32.Found: C, 71.53; H, 6.24; N, 3.14.

[0578] Preparation of2-{4-[2-(3,4,5-Trimethoxy-phenyl)ethyl]phenylamino}-benzoic acid

[0579] To a solution of2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}-benzoic acid methylester (0.62 g, 1.47 mmol) in THF-EtOH (2:1, 6 mL), 1N NaOH solution (4mL) was added, and the reaction mixture was heated to reflux for 5hours. The reaction mixture was then concentrated in vacuo to remove theorganic solvent. The residue was acidified with concentrated HCl (pH 3).This precipitate was collected by filtration, triturated with boilingMeOH—H₂O (4:1) and dried in vacuum at room temperature for 16 hours togive the title compound as a white solid, 0.59 g (1.45 mmol, 98.5%). mp146.0-147.0° C.

[0580] Analysis for C₂₄H₂₅N₁O₅: Calcd: C, 70.75; H, 6.18; N, 3.44.Found: C, 70.54; H, 6.43; N, 3.15.

[0581] Step D: Preparation of2-{4-[2-(3,4,5-Trihydroxyphenyl)ethyl]phenylamino}-benzoic acid

[0582] The title compound was prepared from2-{4-[2-(3,4,5-trimethoxy-phenyl)-ethyl]phenylamino}benzoic acid (0.50g, 1.23 mmol) in CH₂Cl₂ (40 mL) and BBr₃ (10 mL, 1M in CH₂Cl₂, 10.0mmol) using the procedure described in Example 4, Step D. This procedureyielded a green solid, 0.25 g (0.68 mmol, 65%) of the desired product.mp: 160.0-162.0° C.

[0583] Analysis for C₂₁H₁₉N₁O₅.1.44H₂O: Calcd: C, 64.46; H, 5.64; N,3.58. Found: C, 64.07; H, 5.27; N, 3.39.

Example 7

[0584] Preparation of2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}4-methoxy-5-nitrobenzoicacid

[0585] Step A′ (Scheme 2): Preparation of3-(3,4-Dichlorophenyl)-1-(4-nitro-phenyl)propenone

[0586] Sodium hydroxide (7.3 g, 0.18 mol) was dissolved in water (80 mL)and 95% EtOH (80 mL) and cooled to 10° C. with an ice-H₂O bath.3,4-Dichlorobenzaldehyde (31.8 g, 0.18 mol) was added in one portion.After the addition, the mixture was warmed to 15° C.1-(4-Nitrophenyl)ethanone (30.0 g, 0.18 mol) was added at thistemperature with rigorous stirring. After stirring for 5 minutes, thereaction mixture was diluted with 95% EtOH (300 mL). The resulting tanmixture was stirred at room temperature for 30 minutes, then stirredwith an ice-H₂O bath underneath the flask for 2 hours. The light brownsolid was filtered off, washed with H₂O, and air-dried. The solid wasdissolved in hot THF (1.5 L) and treated with charcoal. The resultingmixture was filtered off, and the filtrate was diluted with 95% EtOH(500 mL). This solution was filtered and oven-dried (40° C.) to yield alight brown solid, 38.56 g (0.12 mol, 66%) of the title compound. mp220-223° C.

[0587] Analysis for C₁₅H₉Cl₂NO₃: Calcd: C, 55.93; H, 2.82; Cl, 22.01; N,4.35. Found: C, 55.79; H, 2.93; Cl, 22.16; N, 4.32.

[0588] Step B′ (Scheme 2): Preparation of1-(4-Amino-phenyl)-3-(3,4-dichlorophenyl)propan-1-one

[0589] 3-(3,4-Dichlorophenyl)-1-(4-nitro-phenyl)propenone (34.56 g, 0.11mol) was reduced in the presence of Ra-Ni (3.0 g) in THF (250 mL) at 20°C. to 32° C. (ΔP=33.4 psi) under a hydrogen atmosphere. The reactionmixture was concentrated in vacuo and recrystallized from MeOH (100 mL)to give a light yellow solid, 23.5 g (0.080 mol, 75%) of the desiredproduct. mp 127-129° C.

[0590] Analysis for C₁₅H₁₃Cl₂NO: Calcd: C, 61.24; H, 4.45; N, 4.76; Cl,24.10. Found: C, 60.91; H, 4.60; N, 4.70; Cl, 23.98.

[0591] Step C′ (Scheme 2): Preparation of4-[3-(3,4-Dichlorophenyl)propyl]phenylamine

[0592] A mixture of 1-(4-aminophenyl)-3-(3,4-dichlorophenyl)propan-1-one(20.0 g, 0.068 mol), NH₂NH₂—H₂O (16 mL), and KOH (85%, 5.6 g) inethylene glycol (160 mL) was heated to reflux under a N₂ atmosphere for16 hours. After cooling to room temperature, the reaction mixture waspoured into ice-H₂O and extracted with CH₂Cl₂ (2 L). The layers wereseparated, and the organic layer was dried (Na₂SO₄) and concentrated invacuo to afford an oil. Purification by flash chromatography (silicagel, CH₂Cl₂) yielded an oil, 14.00 g (0.05 mol, 73%) of the desiredproduct.

[0593] Analysis for C₁₅H₁₅Cl₂N: Calcd: C, 64.30; H, 5.40; N, 4.99; Cl,25.31. Found: C, 64.21; H, 5.59; N, 5.24; Cl, 24.87.

[0594] Preparation of 2,4-Difluoro-5-nitrobenzoic acid methyl ester

[0595] Fuming nitric acid 90% (8.5 mL, 0.19 mol) was added with gentlestirring to concentrated sulfuric acid 98% (125 mL) in a 1 L beaker.After stirring for 10 minutes at room temperature, 2,4-difluorobenzoicacid methyl ester (21.9 g, 0.127 mol) was added dropwise. After theaddition, the reaction mixture was allowed to stir gently for 40 minutesat room temperature. The reaction mixture was then poured into ice-H₂O(1 L) and stirred for 10 minutes. The mixture was extracted with EtOAc.The layers were separated, and the organic layer was washed sequentiallywith 1N NaCl, saturated NaHCO₃, H₂O and brine, dried (Na₂SO₄), filteredand concentrated in vacuo to afford a yellow residue. This residue waswashed with 10% EtOAc/hexane, filtered, and dried to yield a pale yellowsolid, 29.0 g (0.133 mol, 82%). mp 78-80° C.

[0596] Analysis for C₈H₅F₂NO₄: Calcd: C, 44.25; H, 2.32; N, 6.45. Found:C, 44.18; H, 2.39; N, 6.14.

[0597] Preparation of 2-Fluoro-4-methoxy-5-nitrobenzoic acid methylester

[0598] A mixture of sodium metal (1.27 g, 0.055 mol) and MeOH (250 mL)was stirred at 0° C. for 10 minutes. This solution was added to asolution of 2-fluoro-5-nitrobenzoic acid methyl ester (10.0 g, 0.046mol) in MeOH (250 mL), and the mixture was stirred for 20 minutes at 0°C. to 5° C. The reaction mixture was then allowed to warm to roomtemperature and stir for 2 hours. The mixture was then filtered to givean off-white precipitate. Recrystallization with CHCl₃ (70 mL) yieldedan off-white crystalline solid, 1.825 g (0.008 mol, 17%) of the titlecompound.

[0599] Analysis for C₉H₈F_(I)N₁O₅: Calcd: C, 47.17; H, 3.52; N, 6.11.Found: C, 47.09; H, 3.47; N, 6.00.

[0600] Preparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoicacid methyl ester

[0601] A mixture of 4-[3-(3,4-dichloro-phenyl)propyl]phenylamine (0.94g, 3.3 mmol), 2-fluoro-4-methoxy-5-nitro-benzoic acid methyl ester (0.75g, 3.3 mmol), and Et₃N (0.46 mL) in CH₃CN (30 mL) was heated to refluxfor 120 hours. The reaction mixture was cooled to room temperature,diluted with CH₂Cl₂ and washed with saturated NaHCO₃. The organic layerwas dried (Na₂SO₄) and concentrated to give a solid. Recrystallizationwith MeOH yielded 0.67 g (1.37 mmol, 42%) of the desired product.

[0602] Analysis for C₂₄H₂₂N₂Cl₂O₅0.42H₂O: Calcd: C, 58.01; H, 4.63. N,5.64; Found: C, 57.61; H, 4.51; N, 5.94.

[0603] Preparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoicacid

[0604] To a solution of2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoicacid methyl ester (0.30 g, 0.061 mol) in THF (5 mL), 1N NaOH (aq.) (2.5mL) was added, and the mixture was stirred for 36 hours at roomtemperature. The solvent was removed, and the residue was acidified withconcentrated HCl to pH 3. The precipitate was collected by filtrationand dried in vacuum for 16 hours. Recrystallization with MeOH gave thetitle compound as an orange solid 0.21 g (0.043 mol, 70%). mp 200-201°C.

[0605] Analysis for C₂₃H₂₀N₂O₅Cl₂.2H₂O: Calcd: C, 57.68; H, 4.29; N,5.85; Cl, 14.81. Found: C, 57.71; H, 4.34; N, 5.58; Cl, 14.56.

Example 8

[0606] Preparation of2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}4-imidazo-1-yl-5-nitrobenzoicacid

[0607] Preparation of2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}4-imidazo-1-yl-5-nitrobenzoicacid methyl ester

[0608] A mixture of 2,4-difluoro-5-nitrobenzoic acid methyl ester (1.63g, 7.5 mmol), imidazole (0.56 g, 8.25 mmol), and Et₃N (1.14 mL, 8.25mmol) in CH₃CN (50 mL) was stirred for 16 hours at room temperature. Tothis deep orange solution, 4-[3-(3,4-dichlorophenyl)propyl]phenylamine(2.10 g, 7.5 mmol) and triethylamine (Et₃N) (1.14 mL, 8.25 mmol) wasadded, and the mixture was heated to reflux for overnight. The reactionmixture was cooled and concentrated in vacuo to afford a residue. Thisresidue was diluted with CH₂Cl₂ and washed with a saturated K₂HCO₃solution. The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo to give a crude oil. Purification by flashchromatography (silica gel, 10% EtOAc/hexane) yielded 1.0 g (1.90 mmol,25%) of the desired product.

[0609] MS: 524.1 (M⁺).

[0610] Preparation of2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-1-1-yl-5-nitrobenzoicacid

[0611] The title compound was prepared from2-{4-[2-[-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoicacid methyl ester (1.0 g, 1.9 mmol), 1N NaOH (2.0 mL) in THF (30 mL)using the procedure described in Example 8. This procedure yielded anorange solid, 0.30 g (0.6 mmol, 32%) of the desired product.

[0612] Analysis for C₂₅H₂₀Cl₂N₄040.2H₂O: Calcd: C, 58.31; H, 3.99; N,10.88; Cl, 13.89. Found: C, 58.34; H, 4.07; N, 10.73; Cl, 13.41.

Example 9

[0613] Preparation of2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino}-benzoic acid

[0614] Preparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-benzoic acid methylester

[0615] The title compound was prepared from4-[3-(3,4-dichlorophenyl)propyl]-phenylamine (600 mg, 2.14 mmol),2-bromobenzoic acid methyl ester (380 mg, 1.78 mmol), cesium carbonate(812 mg, 2.49 mmol), tris(dibenzylideneacetone-dipaladium(0) (49 mg,0.053 mmol) and (S)-(2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%,(S)-tol-BINAP) (54 mg, 0.080 mmol) (Ligand/Pd=1.5) in anhydrous toluene(15 mL) using the procedure described in Example 2, Step C. Thisprocedure yielded an yellow oil, 0.61 g (1.47 mmol, 69%) of the desiredproduct.

[0616] MS: 414 (M⁺), 416 (MH⁺).

[0617] Analysis for C₂₃H₂₁Cl₂O₂N-0.4H₂O: Calcd: C, 65.25; H, 5.23; N,3.30. Found: C, 65.76; H, 5.18; N, 3.10.

[0618] Preparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-benzoic acid

[0619] The title compound was prepared from2-{4-[3-(3,4-dichlorophenyl)-propyl]phenylamino}benzoic acid methylester (0.41 g, 0.99 mmol), 1N NaOH (4.0 mL) in EtOH (4 mL) and THF (4mL) using the procedure described in Example 2. This procedure yielded ayellow solid, 0.32 g (0.80 mmol, 81%) of the desired product. mp120-126° C.

[0620] Analysis for C₂₂H₁₉Cl₂O₂N₁.0.75H₂O: Calcd: C, 64.04; H, 5.00; N,3.39. Found: C, 64.17; H, 4.69; N, 3.18.

Example 10

[0621] Preparation of2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid

[0622] Preparation of (trans)-3-(3,4-Dichlorophenyl)-2-propenal

[0623] A mixture of 3,4-dichlorobenzaldehyde (140.0 g, 0.8 mol) andacetaldehyde (300 mL) was cooled to 5° C. Potassium hydroxide (5.1 g,0.091 mol) was dissolved in hot MeOH (40 mL), and the resulting solutionwas added to the above cooled mixture while maintaining the internaltemperature at 25° C. to 30° C. The mixture was allowed to stir inice-H₂O bath for 40 minutes and then treated with acetic anhydride (400mL). After the addition, the mixture was heated to 100° C. with stirringfor 30 minutes and then cooled to 30° C. To this mixture, 12N HCl/H₂O(102 mL/1.2 L) was added, and the resulting mixture was heated to refluxfor 30 minutes and then cooled to room temperature. This heterogeneousmixture was filtered and washed with H₂O to afford a brown solid. Thecrude product was dissolved in EtOAc and washed with H₂O, dried(Na₂SO₄), and concentrated to dryness. Recrystallization fromhexane/EtOAc (9:1) yielded 76.5 g (0.38 mol, 48%) of the title compound.mp: 91-93° C.

[0624] Analysis for C₉H₆Cl₂O: Calcd: C, 53.77; H, 3.01; Cl, 35.27.Found: C, 53.75; H, 3.10; Cl, 35.58.

[0625] Preparation of (trans),(trans)-1,2-Dichloro-4-[4-(4-nitrophenyl)-1,3-butadienyl]benzene

[0626] A mixture of 4-nitro-benzyl bromide (200.0 g, 0.93 mol) andtriphenylphosphine (244.0 g, 0.93 mol) in CHCl₃ (1.5 L) was heated toreflux for overnight. The reaction mixture was cooled to roomtemperature, concentrated in vacuo to remove CHCl₃ and then suspended inEt₂O and stirred rigorously. The suspension was filtered, and theoff-white solid was washed with Et₂O, dried at 80° C. for 16 hours togive 433.0 g (0.91 mol, 98%) ofbromo[(4-nitrophenyl)methyl]triphenylphosphorane. A solution ofbromo[(4-nitrophenyl)methyl]triphenylphosphorane (100.0 g, 0.23 mol) indry THF (500 mL) was cooled to 5° C. n-Butyl lithium (n-BuLi) (2.4 M, 96mL, 0.23 mol) was added dropwise to maintain the temperature between 5°C. to 10° C. The cooling bath was then removed, and the reaction mixturewas allowed to warm to room temperature. After 4 hours, a solution of(trans)-3-(3,4-dichlorophenyl)-2-propenal (36.2 g, 0.18 mol) in THF (100mL) was added dropwise, and the resulting mixture was stirred at roomtemperature for 16 hours. The mixture was filtered, and the filtrate wasconcentrated in vacuo to give a residue. Purification by flashchromatography (silica gel, 20% EtOAc/hexane) yielded 16.0 g (0.05 mol,28%) of the desired product. mp 125-135° C.

[0627] Analysis for C₁₆H₁₁Cl₂NO₂: Calcd: C, 60.02; H, 3.46; N, 4.37, Cl,22.15. Found: C, 59.77; H, 3.47; N, 4.40; Cl, 22.39.

[0628] Preparation of 4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamine

[0629] The title compound was prepared from (trans),(trans)-1,2-dichloro-4-[4-(4-nitrophenyl)-1,3-butadienyl]benzene (15.42g, 0.048 mol), Ra-Ni (1 g) at 20° C. to 26° C. (ΔP=19.3 psi) under ahydrogen atmosphere in THF (75 mL) and MeOH (75 mL) using the proceduredescribed in Example 1, Step B. This procedure yield a solid, 10.97 g(0.037 mol, 78%) of the desired product. mp 50-52° C.

[0630] Analysis of C₁₆H₁₇N₁ Cl₂: Calcd: C, 65.32; H, 5.82; N, 4.76.Found: C, 65.43; H, 5.84; N, 4.61.

[0631] Preparation of2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid

[0632] The title compound, mp 98-105° C., was prepared from4-[4-(3,4-dichlorophenyl)butyl]phenylamine (0.50 g, 1.7 mmol),2-chlorobenzoic acid (0.24 g, 1.56 mmol), anhydrous potassium carbonate(0.71 g, 5.15 mmol), copper powder (0.21 g, 3.28 mmol), and copper(I)chloride (0.015 g, 0.15 mmol) in dry DMF (5 mL) using the proceduredescribed in Example 1, Step C, Method B.

Example 11

[0633] Preparation of2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoic acid

[0634] A mixture of 2-fluoro-5-nitrobenzoic acid (1.85 g, 0.01 mol),4-[4-(3,4-dichlorophenyl)butyl]-phenylamine (2.94 g, 0.01 mol) and Et₃N(2.80 mL) in acetonitrile (110 mL) was heated to reflux for 48 hours.The reaction mixture was cooled and concentrated in vacuo to remove thesolvent. The residue was dissolved in CH₂Cl₂ and washed with dilutedHCl. The organic layer was dried (Na₂SO₄), concentrated in vacuo to givea crude solid. Purification by flash chromatography (silica gel, CH₂Cl₂)yielded 1.40 g (0.003 mol, 30%) of the desired product.

[0635] Analysis for C₂₃H₁₉N₂O₄Cl₂: Calcd: C, 60.27; H, 4.18; N, 6.11;Cl, 14.47. Found: C, 60.16; H, 4.41; N, 6.09; Cl, 15.69.

Example 12

[0636] Preparation of2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}-3,5-dinitrobenzoic acid

[0637] To a cooled (0° C.) solution of4-[4-(3,4-dichlorophenyl)butyl]-phenylamine (1.47 g, 5.0 mmol) and DBU(0.75 mL, 7.5 mmol) in acetonitrile (25 mL), a solution of2-fluoro-2,5-dinitrobenzoic acid (1.15 g, 5.0 mmol) in acetonitrile (15mL) was added dropwise. After stirring for 30 minutes at 0° C., thereaction mixture was neutralized with dilute HCl and extracted withEtOAc, dried (Na₂SO₄), filtered and concentrated in vacuo to afford acrude residue. Recrystallization with EtOH yielded a bright orangesolid, 2.06 g (4.1 mmol, 82%) of the title compound.

[0638] Analysis for C₂₃H₁₉Cl₂N₃O₆: Calcd: C, 54.77; H, 3.80; N, 8.33;Cl, 14.06. Found: C, 54.68; H, 4.00; N, 8.12; Cl, 13.81.

Example 13

[0639] Preparation of2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid

[0640] Preparation ofBromo[(3,4-dichlorophenyl)methyl]triphenylphosphorane

[0641] A mixture of 4-bromomethyl-1,2-dichlorobenzene (2.40 g, 0.01mol), and triphenylphosphine (5.24 g, 0.02 mol) in toluene (30 mL) wasstirred for 16 hours at room temperature. The solid was filtered, rinsedwith toluene, and oven-dried at room temperature to yield a whitepowder, 3.95 g (0.0078 mol, 78%) of the desired product.

[0642]¹H NMR [dimethylsulfoxide (DMSO):ppm]:7.89-7.61 (m, 15H), 7.50 (d,J=8.3 Hz, 1H), 7.04 (t, J=2.3 Hz, 1H), 6.97 (m, 1H), 5.20 (d, J=15.9 Hz,2H).

[0643] Preparation of 4-(4-Nitrophenyl)butyraldehyde

[0644] To a cooled solution (−70° C.) of oxalyl chloride (2.0 M inCH₂Cl₂, 14.1 mL, 28.2 mmol), dimethylsulfoxide (DMSO) (4.40 g, 56.32mmol) in CH₂Cl₂ (20 mL) was added dropwise. The resulting reactionmixture was then stirred for 30 minutes at −70° C. under a nitrogenatmosphere. A solution of 4-(4-nitrophenyl)butan-1-ol (5.00 g, 25.6mmol) in CH₂Cl₂ (3 mL) was added dropwise, and the reaction mixture wasstirred for 1 hour at −70° C. Et₃N (16 mL, 115 mmol) was added, and thereaction mixture was then allowed to gradually warm to room temperatureand stir for 30 minutes. The mixture was then quenched with H₂O andextracted with EtOAc. The organic layers were washed with 0.1N HClsolution, H₂O, brine, dried (Na₂SO₄), filtered, and concentrated invacuo to give a lightly brown oil. Purification by flash chromatography(silica gel, 50% EtOAc/hexane) yielded 3.20 g (16.56 mmol, 65%) of thedesired product.

[0645]¹H NMR (DMSO:ppm): 9.75 (s, 1H), 8.12 (d, J=8.3 Hz, 2H), 7.30 (d,J=8.3 Hz, 2H), 2.72 (t, J=7.7 Hz, 2H), 2.47 (t, J=7.1 Hz, 2H), 1.94 (m,2H).

[0646] Preparation of1,2-Dichloro-4-[5-(4-nitrophenyl)-1-pentenyl]benzene

[0647] A solution ofbromo[(3,4-dichlorophenyl)methyl]triphenylphosphorane (3.95 g, 7.9 mmol)in dry THF (20 mL) was cooled to 0° C. LHDMS (1.0 MITHF, 9 mL, 9.0 mol)was added dropwise to maintain the temperature at 0° C. After stirringfor 30 minutes, a solution of 4-(4-nitro-phenyl)butyraldehyde (1.45 g,7.5 mmol) in THF (5 mL) was added dropwise, and the mixture was allowedto warm to room temperature within 2 hours. The mixture was thenquenched with H₂O and extracted with EtOAc. The organic layers werewashed with 0.1N HCl solution, H₂O, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give a lightly brown oil. Purification by flashchromatography (silica gel, 10% EtOAc/hexane) yielded 2.5 g (7.4 mmol,99%) of the desired product.

[0648] MS: 335 (M⁺), 337 (MH⁺).

[0649] Preparation of 4-[5-(3,4-Dichlorophenyl)pentyl]phenylamine

[0650] The title compound was prepared from1,2-dichloro-4-[5-(4-nitrophenyl)-1-pentenyl]benzene (2.5 g, 7.4 mmol),Ra-Ni (1 g) in THF (50 mL) at 25° C. to 40° C. (ΔP=9.9 psi) using theprocedure described in Example 1, Step B. This procedure yielded 1.06 g(3.4 mmol, 46%) of the desired product.

[0651]¹H NMR (DMSO:ppm): 7.45 (d, J=8.3 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H),7.12 (m, 1H), 6.74 (d, J=8.3 Hz, 2H), 6.40 (d, J=8.3 Hz, 2H), 4.73 (s,2H), 2.50 (t, J=7.7 Hz, 2H), 2.31 (t, J=7.6 Hz, 2H), 1.6-1.5 (m, 4H),1.5-1.4 (m, 2H).

[0652] Preparation of2-{4-[5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-5-nitrobenzoic acid

[0653] To a cooled (−78° C.) solution of4-[5-(3,4-dichlorophenyl)pentyl]-phenylamine (0.231 g, 0.75 mmol) in THF(2 mL), LHDMS (2.25 mL, 1 M in hexane, 2.25 mmol) was added dropwise.The reaction mixture was allowed to stir at −78° C. for 10 minutes. Asolution of 2-fluoro-5-nitrobenzoic acid (0.139 g, 0.75 mmol) in THF (2mL) was added dropwise, and this solution was stirred for 30 minutes at−78° C. The reaction mixture was allowed to gradually warm to roomtemperature and stir for 2 hours under N₂ atmosphere. The reactionmixture was diluted with EtOAc, and acidified with 1N HCl (pH 3). Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo toyield a brown residue. Purification by flash chromatography (silica gel,2% MeOH/CH₂Cl₂) then recrystallization with MeOH yielded 265 mg (0.56mmol, 75%) of the desired product. mp 147-148° C.

[0654] Analysis for C₂₄H₂₂Cl₂N₂040.37H₂O: Calcd: C, 60.05; H, 4.77; N,5.84. Found: C, 59.67; H, 4.64; N, 5.51.

Example 14

[0655] Preparation of2-{4-[5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoicacid

[0656] Preparation of2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoicacid methyl ester

[0657] The title compound was prepared from4-[5-(3,4-dichlorophenyl)pentyl]phenylamine (231 mg, 0.75 mmol), LHDMS(6.28 mL, 1 M in THF, 6.28 mmol) and 2-fluoro-4-methoxy-5-nitrobenzoicacid methyl ester (172 g, 0.75 mmol) in THF (5 mL) using the proceduredescribed in Example 13. Purification by flash chromatography (silicagel, 10% EtOAc/hexane) yielded 145 mg (0.28 mmol, 37%) of the desiredproduct.

[0658] MS: 515.2 (M⁺), 517.2 (MH⁺).

[0659] Preparation of2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}4-methoxy-5-nitrobenzoicacid

[0660] The title compound was prepared from2-{4-[5-(3,4-dichlorophenyl)-pentyl]phenylamino}4-methoxy-5-nitrobenzoicacid methyl ester (145 mg, 0.28 mmol) and 1N NaOH (aq.) (0.56 mL) in THF(1.2 mL) using the procedure described in Example 2. Purification byflash chromatography (silica gel, 10% MeOH/CH₂Cl₂), thenrecrystallization with MeOH yielded 58 mg (0.12 mmol, 41%) of thedesired product. mp 192-193° C.

[0661] Analysis for C₂₅H₂₄Cl₂N₂O₅: Calcd: C, 59.65; H, 4.81; N, 5.56.Found: C, 59.29; H, 4.58; N, 5.36.

Example 15

[0662] Preparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid

[0663] Preparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acidmethyl ester

[0664] The title compound was prepared from4-[3-(3,4-dichlorophenyl)propyl]-phenylamine. (420 mg, 1.50 mmol),2-bromobenzoic acid methyl ester (310 mg, 1.25 mmol), cesium carbonate(569 mg, 1.75 mmol), tris(dibenzylideneacetone-dipaladium(0) (34 mg,0.037 mmol) and (S)-(2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%,(S)-tol-BINAP) (38 mg, 0.056 mmol) (Ligand/Pd=1.5) in anhydrous toluene(15 mL) using the procedure described in Example 2, Step C. Thisprocedure yielded an orange solid 0.51 g (1.11 mmol, 74%) of the desiredproduct. mp 117-118° C.

[0665] MS: 457.1 (M⁺); 459.1 (MH⁺)

[0666] Preparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid

[0667] The title compound was2-{4-[3-(3,4-dichlorophenyl)-propyl]phenylamino}-5-nitrobenzoic acidmethyl ester (0.50 g, 1.09 mmol), 2N NaOH (5.0 mL) in EtOH (2 mL) andTHF (4 mL) using the procedure described in Example 2. This procedureyielded an orange solid, 0.49 g (1.10 mmol, 100%) of the desiredproduct. mp 153-155° C.

[0668] MS: 443.2 (M⁺), 445.2 (MH⁺)

Example 16

[0669] Preparation of2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid

[0670] Preparation of2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino)-5-nitrobenzoic acidmethyl ester

[0671] The title compound was prepared from4-[2-(3,4-dimethylphenyl)ethyl]-benzenamine (1.0 g, 4.43 mmol),2-bromo-5-nitrobenzoic acid methyl ester (0.96 g, 3.69 mmol), cesiumcarbonate (1.68 g, 5.17 mmol), tris(dibenzylideneacetone-dipaladium(0)(101 mg, 0.11 mmol) and(S)-(2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%, (S)-tol-BINAP)(113 mg, 0.17 mmol) (Ligand/Pd=1.5) in anhydrous toluene (32 mL) usingthe procedure described in Example 2, step C. This procedure yielded anyellow solid, 1.31 g (3.24 mmol, 73%) of the desired product. mp115-117° C.

[0672] MS: 405 (M⁺)

[0673] Analysis for C₂₄H₂₄O₄N₂ 0.25H₂O: Calcd: C, 71.27; H, 5.98; N,6.93. Found: C, 70.48; H, 6.03; N, 6.85.

[0674] Preparation of2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid

[0675] The title compound was prepared2-{4-[2-(3,4-dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acidmethyl ester (1.12 g, 2.76 mmol), 1N NaOH (50 mL) in EtOH (50 mL) andTHF (50 mL) using the procedure described in Example 2. This procedureyielded a yellow solid, 1.03 g (2.63 mmol, 81%) of the desired product.mp 214-216° C.

[0676] Analysis for C₂₃H₂₂O₄N₂.0.25H₂O: Calcd: C, 69.99; H, 5.74; N,7.18. Found: C, 69.90; H, 5.82; N, 6.81.

Example 17

[0677] Preparation of2-[[4-[2-(4-Chloro-3-trifluromethylphenyl)ethyl]phenyl]amino-benzoicacid

[0678] Step A (Scheme 1): Preparation oftrans-1-Chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene

[0679] A mixture of p-nitrophenylacetic acid (51.85 g, 0.29 mol) and4-chloro-3-trifluoromethylbenzaldehyde (47.85 g, 0.23 mol) in piperidine(19.5 g, 0.23 mol) was heated under N₂ atmosphere to 150° C. to 160° C.for 1 hour. The reaction mixture was cooled to 80° C. to 100° C. andrefluxing i-PrOH (150 mL) was added. The mixture was continued to coolto room temperature and then placed under refrigeration for 5 hours. Thecrystalline precipitate was filtered off, rinsed with cold i-PrOH, anddried at room temperature in a vacuum oven overnight to yieldtrans-1-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene asan orange solid, 22.53 g (68.75 mmol, 30%). mp 173-174° C.

[0680] MS: 327.0 (M⁺)

[0681] Step B (Scheme 1): Preparation of4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]-benzenamine

[0682] The title compound was prepared fromtrans-1-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene(22.53 g, 0.069 mol) and Ra-Ni (22 g) in THF (0.5 L) at 18° C. to 29° C.(ΔP=20.5 psi) under a hydrogen atmosphere using the procedure describedin Example 1, Step B. This procedure yielded a white solid, 20.0 g(66.73 mmol, 97%) of the desired product. mp 62-64° C.

[0683] MS: 298.1 (M⁺)

[0684] Preparation of2-[[4-[2-(4-Chloro-3-trifluromethylphenyl)ethyl]phenyl]-aminobenzoicacid

[0685] To a cold solution of4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]-benzenamine (4.33 g, 14.45mmol) in THF (50 mL) at −78° C., was added LHMDS (43.35 mL, 43.35 mmol)(1M/THF) dropwise. Allowed the reaction mixture to stir for 10 minutesat −78° C. A solution of 2-fluorobenzoic acid (2.02 g, 14.45 mmol) inTHF (50 mL) was added dropwise. The mixture was stirred for 2 hours at−78° C., then warmed to room temperature and let stir for additional 3hours. The reaction mixture was concentrated in vacuo (40° C.) to removethe organic solvent. This residue was acidified to pH 3 with 3N HCl(aq.). This precipitate was collected by filtration, rinsed with 10% HCl(40 mL), and dried in vacuum for overnight to give as a pale solid, 4.3g (10.24 mmol, 70%) of the desired product. mp 150-152° C.

[0686] Analysis for C₂₂H₁₇O₂N₁CIF₃ 0.59H₂O: Calcd: C, 61.39; H, 4.26; N,3.25. Found: C, 61.01; H, 4.34; N, 3.30.

Example 18

[0687] Preparation of 2-[4-(3,4-Dichlorophenyl)phenylamino]benzoic acid

[0688] Preparation of o-Bromobenzoic acid potassium salt

[0689] To a solution of o-bromobenzoic acid (201.03 g, 1.0 mol) in MeOH(500 mL), K₂CO₃ (69 g, 1.0 mol) was added. The mixture was concentratedto give the desired product (239.1 g, 1.0 mol, 100%).

[0690] Preparation of 2-[(4-Iodophenyl)amino]benzoic acid

[0691] A mixture of o-bromobenzoic acid potassium salt (47.8 g, 0.2mol), 4-iodoaniline (43.8 g, 0.2 mol), K₂CO₃ (13.8 g, 0.1 mol), andcupric acetate (2.87 g, 6%) in diglyme (100 mL) was heated to reflux for30 minutes. The reaction mixture was diluted with H₂O (1.0 L) andfiltered. The filtrate was acidified with diluted AcOH. The resultingprecipitate was collected by filtration, washed with H₂O and dried in avacuum at 50° C. for 16 hours. Recrystallization from EtOAc gave thedesired product, a solid (29.7 g, 0.087 mol, 44%). mp 205-206° C.

[0692] Analysis for C₁₃H₁₀N₁O₂1: Calcd: C, 45.05; H, 2.97; N, 4.13.Found: C, 45.05; H, 2.97; N, 3.92.

[0693] Preparation of 2-[4-(3,4-Dichlorophenyl)phenylamino]benzoic acid

[0694] A mixture of 3,4-dichlorophenylboronic acid (880 mg, 2.3 mmol),2-[(4-iodophenyl)amino]benzoic acid (339 mg, 1 mmol), PdCl₂dppf-CH₂Cl₂[1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride, complexedwith dichloromethane (1:1)] (67 mg, 0.082 mmol), K₂CO₃ (829 mg, 6 mmol),and H₂O (2 mL) in dioxane (15 mL) was heated to reflux for 1 hour. Thereaction mixture was diluted with EtOAc and filtered. The filtrate wastreated with 1N HCl, washed with H₂O, brine, dried (Na₂SO₄), andconcentrated in vacuum to give a yellow solid. Purification by flashchromatography (silica gel, 10% MeOH/CH₂Cl₂) yielded 272 mg (0.76 mmol,76%) of the desired product.

[0695] mp>220° C.

[0696] Analysis for C₁₉H₁₃O₂N₁Cl₂: Calcd: C, 63.23; H, 3.71; N, 3.88.Found: C, 62.95; H, 3.73; N, 3.63.

[0697] By following the general procedures described above, thefollowing additional invention compounds were prepared:

Example 19

[0698] 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid

[0699] MS: 403 (M⁺).

[0700] Analysis for C₂₆H₃₀N₂O₂.40 mol H₂O: Calcd: C, 69.31; H, 6.87; N,6.12. Found: C, 69.29; H, 7.04; N, 6.35.

Example 20

[0701] 2-{4-[3-(4-Nitrophenyl)propyl]phenylamino}benzoic acid. mp150-153° C.

[0702] MS: 376 (M⁺).

Example 21

[0703] 2-(4-[3-(3-Nitrophenyl)propyl]phenylamino}benzoic acid. mp164-167° C.

[0704] MS: 376 (M⁺).

[0705] Analysis for C₂₂H₂₀N₂O₄.2.20 mol H₂O: Calcd: C, 63.51; H, 5.91;N, 6.73. Found: C, 63.56; H, 5.45; N, 6.46.

Example 22

[0706] 2-{4-[3-(4-Aminophenyl)propyl]phenylamino}benzoic acid. mp110-112° C.

[0707] MS: 347 (M⁺1⁺).

Example 23

[0708] 2-{4-[3-(3-Aminophenyl)propyl]phenylamino}benzoic acid. mp 109°C.

[0709] MS: 333 (M⁺1⁺).

Example 24

[0710] 2-{4-[2-(4-Aminophenyl)phenylamino}benzoic acid. mp 198-201° C.

[0711] MS: 333 (M⁺1⁺).

[0712] Analysis for C₂₁H₂₀N₂O₂₀-1 mol H₂O: Calcd: C, 75.47; H, 6.09; N,8.38. Found: C, 75.32; H, 6.12; N, 8.27. Found: C, 75.32; H, 6.12; N,8.27.

Example 25

[0713] 2-{4-[2-(4-Dipropylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride. mp 176-177° C.

[0714] MS: 417 (M⁺1⁺).

[0715] Analysis for C₂₇H₃₂N₂O₂: Calcd: C, 71.59; H, 7.34; N, 6.18; Cl,7.83. Found: C, 71.31; H, 7.24; N, 6.19; Cl, 7.74.

Example 26

[0716] 2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride monohydrate

[0717] MS: 389 (M+1⁺).

[0718] Analysis for C₂₅H₂₈N₂O₂HCl.H₂O: Calcd: C, 67.78; H, 7.05; N,6.32; Cl, 8.00. Found: C, 67.83; H, 7.01; N, 6.30; Cl, 7.75.

Example 27

[0719] 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenylamino}benzoic acid

[0720] MS: 431(M⁺1⁺).

[0721] Analysis for C₂₈H₃₄N₂020.2H₂O: Calcd: C, 77.46; H, 7.99; N, 6.45.Found: C, 77.43; H, 7.86; N, 6.40.

Example 28

[0722] 2-{4-[3-(3-Dimethylaminophenyl)propyl]phenylamino}benzoic acid.mp 115-117° C.

[0723] MS: 374 (M⁺), 375 (M⁺1⁺).

[0724] Analysis for C₂₄H₂₆N₂O₂.1H₂O: Calcd: C, 76.61; H, 7.02; N, 7.44.Found: C, 76.57; H, 7.21; N, 7.47.

Example 29

[0725] 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoic acid. mp133° C.

[0726] MS: 375 (M⁺1⁺).

[0727] Analysis for C₂₄H₂₆N₂O₂.0.1H₂O: Calcd: C, 76.61; H, 7.02; N,7.44. Found: C, 76.62; H, 7.06; N, 7.36.

Example 30

[0728]2-(N-{4-[3-(4-Diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoicacid

[0729] MS: 431 (M+1⁺).

[0730] Analysis for C₂₈H₃₄N₂O₂: Calcd: C, 78.10; H, 7.96; N, 6.51.Found: C, 78.02; H, 8.17; N, 6.50.

Example 31

[0731] 2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino}benzoic acid. mp95.5-97.5° C.

[0732] Analysis for C₃₅H₃₂N₂O₂: Calcd: C, 82.00; H, 6.29; N, 5.46.Found: C, 81.81; H, 6.58; N, 5.44.

Example 32

[0733] 2-{4-[3-(3-Diethylaminophenyl)propyl]phenylamino}benzoic acid

[0734] MS: 403 (M+1⁺).

[0735] Analysis for C₂₆H₃₀N₂O₂₀-1H₂O: Calcd: C, 77.23; H, 7.53; N, 6.93.Found: C, 77.14; H, 7.82; N, 6.88.

Example 33

[0736] 2-{4-[2-(3-Aminophenyl)ethyl]phenylamino}benzoic acid. mp182-184° C.

[0737] MS: 333 (M+1⁺).

[0738] Analysis for C₂₁H₂₀N₂O₂.0.25H₂O: Calcd: C, 74.87; H, 6.13; N,8.43. Found: C, 74.86; H, 6.16; N, 8.32.

Example 34

[0739] 2-{4-[3-(4-Dimethylaminophenyl)propyl]phenylamino}benzoic acid

[0740] MS: 375 (M+1⁺).

[0741] Analysis for C₂₄H₂₆N₂020.1H₂O: Calcd: C, 76.61; H, 7.02; N, 7.44.Found: C, 76.52; H, 7.22; N, 7.49.

Example 35

[0742] 2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino}benzoic acid. mp224° C.

[0743] MS: 375 (M⁺1⁺).

Example 36

[0744] 2-{4-[2-(3-Acetylaminophenyl)ethyl]phenylamino}benzoic acid. mp213-215° C.

[0745] MS: 375 (M⁺1⁺).

Example 37

[0746] 2-{4-[2-(3-Dipropylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride. mp 189-193° C.

[0747] MS: 417 (M+1⁺).

[0748] Analysis for C₂₇H₃₂N₂O₂HCl: Calcd: C, 71.58; H, 7.34; N, 6.18;Cl, 7.83. Found: C, 71.48; H, 7.35; N, 6.10; Cl, 7.66.

Example 38

[0749] 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride. mp 175-180° C.

[0750] MS: 445 (M⁺).

[0751] Analysis for C₂₉H₃₆N₂O₂HCl: Calcd: C, 72.40; H, 7.75; N, 5.82;Cl, 7.37. Found: C, 72.61; H, 7.95; N, 5.78; Cl, 7.23.

Example 39

[0752] 2-{4-[3-(4-Acetylaminophenyl)propyl]phenylamino}benzoic acid. mp176-178° C.

[0753] MS: 389 (M+1⁺).

Example 40

[0754] 2-{4-[3-(3-Acetylaminophenyl)propyl]phenylamino}benzoic acid. mp140-145° C.

[0755] MS: 389 (M+1⁺).

Example 41

[0756] 2-{4-[2-(3-Diethylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride. mp 166-171]C.

[0757] MS: 389 (M+1⁺).

[0758] Analysis for C₂₅H₂₈N₂O₂HCl: Calcd: C, 70.66; H, 6.88; N, 6.59;Cl, 8.34. Found: C, 70.48; H, 6.89; N, 6.57; Cl, 18.39.

Example 42

[0759] 2-{4-[2-(3-Piperidin-1-ylphenyl)ethyl]phenylamino}benzoic acidmonohydrochloride. mp 187-193° C.

[0760] MS: 401 (M+1⁺).

[0761] Analysis for C₂₆H₂₈N₂O₂HCl: Calcd: C, 71.46; H, 6.69; N, 6.41;Cl, 8.11. Found: C, 71.28; H, 6.73; N, 6.35; Cl, 8.30.

Example 43

[0762] 2-{4-[3-(4-Dipropylaminophenyl)propyl]phenylamino}benzoic acid

[0763] MS: 431 (M⁺1⁺).

[0764] Analysis for C₂₈H₃₄N₂O₂: Calcd: C, 78.10; H, 7.96; N, 6.51.Found: C, 77.91; H, 8.03; N, 6.43.

Example 44

[0765] 2-{4-[3-(4-Dibutylaminophenyl)propyl]phenylamino}benzoic acid

[0766] MS: 459 (M⁺1⁺).

[0767] Analysis for C₃₀H₃₈N₂O₂: Calcd: C, 78.56; H, 8.35; N, 6.11.Found: C, 78.40; H, 8.50; N, 6.19.

Example 45

[0768] 2-{4-[3-(3-Dibutylaminophenyl)propyl]phenylamino}benzoic acid

[0769] MS: 459 (M+1⁺).

[0770] Analysis for C₃₀H₃₈N₂O₂: Calcd: C, 78.56; H, 8.35; N, 6.11.Found: C, 78.40; H, 8.43; N, 6.11.

Example 46

[0771] 2-(4-{3-[4-(1H-Pyrrol-1-yl)phenyl]propyl}phenylamino) benzoicacid. mp 131-136° C.

[0772] MS: 397 (M+1⁺).

[0773] Analysis for C₂₆H₂₄N₂O₂.2H₂O: Calcd: C, 78.05; H, 6.15; N, 7.00.Found: C, 77.95; H, 6.17; N, 7.08.

Example 47

[0774] 2-{4-[3-(4-Piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid

[0775] MS: 415 (M+1⁺).

[0776] Analysis for C₂₇H₃₀N₂020.2H₂O: Calcd: C, 77.55; H, 7.33; N, 6.70.Found: C, 77.37; H, 7.35; N, 6.63.

Example 48

[0777] 2-{4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino}benzoicacid. mp 57-62° C.

[0778] MS: 431 (M+1⁺).

[0779] Analysis for C₂₇H₃₀N₂O₃.0.3H₂O: Calcd: C, 74.39; H, 7.07; N,6.43. Found: C, 74.23; H, 6.97; N, 6.27.

Example 49

[0780] 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino}benzoic acid. mp236-239° C.

[0781] MS: 375 (M⁺).

Example 50

[0782] 2-{4-[3-(4-Diethyl aminomethylphenyl)propyl]phenylamino}benzoicacid. mp 137° C.

[0783] MS: 417 (M+1⁺).

Example 51

[0784] 2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino}benzoic acid

[0785] MS: 389 (M+1⁺).

[0786] Analysis for C₂₅H₂₈N₂O₂ 0.2H₂O: Calcd: C, 76.58; H, 7.30; N,7.14. Found: C, 76.61; H, 7.29; N, 7.03.

Example 52

[0787] 2-{4-(3-(3-Propylaminophenyl)propyl]phenylamino}benzoic acid

[0788] MS: 389 (M+1⁺).

[0789] Analysis for C₂₅H₂₈N₂020.1H₂O: Calcd: C, 76.93; H, 7.28; N, 7.18.Found: C, 76.85; H, 7.44; N, 7.06.

Example 53

[0790] 2-{4-[3-(4-Pyrrolidin-1-yl-phenyl)-propyl]-phenylamino}-benzoicacid. mp 171-177° C.

[0791] MS: 401 (M+1⁺).

[0792] Analysis for C₂₆H₂₈N₂020.2H₂O: Calcd: C, 77.27; H, 7.08; N, 6.93.Found: C, 77.09; H, 6.97; N, 6.96.

Example 54

[0793] 2-{4-[3-(3-Piperidin-1 yl-phenyl)-propyl]-phenylamino}-benzoicacid. mp 59-61° C.

[0794] MS: 415 (M+1⁺).

[0795] Analysis for C₂₇H₃₀N₂O₂.3H₂O: Calcd: C, 77.22; H, 7.34; N, 6.67.Found: C, 77.18; H, 7.25; N, 6.49.

Example 55

[0796]{5-[(1-Butyl-1,2,3,4-tetrahydro-6-quinolyl)methylidene]4-oxo-2-thioxothiazolidin-3-yl}aceticacid. mp 222-224° C.

[0797] MS: 391 (M+1⁺).

Example 56

[0798]{5-[(1-Butyl-2,3-dihydro-1H-indol-5-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}aceticacid. mp>250° C.

[0799] MS: 377 (M+1⁺).

[0800] Analysis for C₁₈H₂₀N₂O₃S₂.0.4H₂O: Calcd: C, 56.34; H, 5.46; N,7.30; S, 16.71. Found: C, 56.27; H, 5.18; N, 7.31; S, 16.74.

Example 57

[0801]3-{5-[(1-Butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}propanoicacid. mp 214-215° C.

[0802] MS: 405 (M+1⁺).

Example 58

[0803]4-{5-[(1-Butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}butanoicacid. mp 152-154° C.

[0804] MS: 417 (M⁻1⁺), 418 (M⁺), 419 (M+1⁺).

[0805] Analysis for C₂₁H₂₆N₂O₃S₂.2H₂O: Calcd: C, 59.74; H, 6.30; N,6.64; S, 15.19. Found: C, 59.59; H, 6.16; N, 6.52; S, 15.38.

Example 59

[0806]2-{4-[3-(3,4-Dichloro-phenyl)-propyl]phenylamino}-5-methyl-benzoic acid.mp 98-99° C.

[0807] MS: 414 (M⁺).

Example 60

[0808]N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)-methanesulfonamidewas prepared by reacting the product from Example 9 withmethanesulfonamide. mp 53-61° C.

[0809] Analysis for C₂₃H₂₂Cl₂N₂O₃S_(0.13)H₂O: Calcd: C, 57.58; H, 4.68;N, 5.84. Found: C, 57.20; H, 4.66; N, 5.51.

Example 61

[0810] 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid. mp 214-216° C.

[0811] Analysis for C₂₃H₂₂N₂040.25H₂O: Calcd: C, 69.99; H, 5.74; N,7.18. Found: C, 69.90; H, 5.82; N, 6.81.

Example 62

[0812] 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid.mp 239-244° C.

[0813] MS: 439 (MH⁺).

Example 63

[0814]2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid. mp 207-209° C.

[0815] Analysis for C₂₂H₁₆ClF₃N₂O₄: Calcd: C, 56.85; H, 3.47; N, 6.03.Found: C, 56.75; H, 3.71; N, 5.83.

Example 64

[0816] 5-Amino-2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoicacid was prepared by reacting the product from Example 2 with hydrogengas in the presence of Raney nickel. mp 137-142° C.

[0817] Analysis for C₂₁H₁₈Cl₂N₂O₂.0.96 mol THF: Calcd: C, 63.94; H,4.72; N, 6.00. Found: C, 64.33; H, 4.91; N, 6.35.

Example 65

[0818] 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid. mp 198-202° C.

[0819] Analysis for C₂₁H₁₈N₂040.11H₂O: Calcd: C, 69.22; H, 5.04; N,7.69. Found: C, 69.59; H, 5.27; N, 7.22.

Example 66

[0820]2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoicacid. mp 148-150° C.

[0821] Analysis for C₂₂H₁₇F₄NO₂: Calcd: C, 65.51; H, 4.25; N, 3.47.Found: C, 65.51; H, 4.13; N, 3.46.

Example 67

[0822] 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid mp 203-208° C.

[0823] Analysis for C₂₁H₁₆F₂N₂O₄: Calcd: C, 63.32; H, 4.05; N, 7.03.Found: C, 62.94; H, 4.37; N, 6.87.

Example 68

[0824]{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-[2-(1H-tetrazol-5-yl)-phenyl]-aminewas prepared as described in Example 1, using a tetrazole fluorointermediate that was synthesized from commercially available2-fluorobenzonitrile and sodium azide under standard reactionconditions. mp 129 shrink, 152-157° C.

[0825] Analysis for C₂₁H₁₇Cl₂N₅.15 EtOAc0.15 Hexane: Calcd: C, 61.80; H,4.64; N, 16.12. Found: C, 61.61; H, 4.28; N, 15.83.

Example 69

[0826]2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid. mp 190-193° C.

[0827] Analysis for C₂₂H₁₆F₄N₂O₄: Calcd: C, 58.93; H, 3.60; N, 6.25.Found: C, 58.69; H, 3.42; N, 6.57.

Example 70

[0828] 2-(4-Phenethyl-phenylamino)-benzoic acid. mp 173-182° C.

[0829] Analysis for C₂₁H₁₉NO₂: Calcd: C, 79.47; H, 6.03; N, 4.41. Found:C, 79.42; H, 5.97; N, 4.47. Found: C, 79.59; H, 6.03; N, 4.50.

Example 71

[0830]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-fluoro-benzoic acid.mp 180-182° C.

[0831] Analysis for C₂₁H₁₆Cl₂FNO₂.06H₂O: Calcd: C, 62.23; H, 4.01; N,3.46. Found: C, 61.83; H, 4.04; N, 3.29.

Example 72

[0832] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-nicotinic acid.mp 168-171° C.

[0833] Analysis for C₂₀H₁₆Cl₂N₂O₂: Calcd: C, 62.03; H, 4.16; N, 7.23.Found: C, 62.11; H, 4.17; N, 7.07.

Example 73

[0834] 2-{4-[2-(3-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid. mp 192.5-194.5° C.

[0835] Analysis for C₂₁H₁₇ClN₂O₄: Calcd: C, 63.56; H, 4.32; N, 7.06.Found: C, 63.83; H, 4.62; N, 6.79.

Example 74

[0836] 2-{4-[2-(4-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid. mp 210-212° C.

[0837] Analysis for C₂₁H₁₇ClN₂040.26H₂O: Calcd: C, 62.82; H, 4.40; N,6.98. Found: C, 62.51; H, 4.34; N, 6.58.

Example 75

[0838]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid.mp 153-160° C.

[0839] Analysis for C₂₂H₁₉Cl₂NO_(20.61)H₂O: Calcd: C, 64.25; H, 4.96; N,3.41. Found: C, 63.87; H, 4.64; N, 3.55.

Example 76

[0840] 2-{4-[2-(2-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid. mp 236-238° C.

Example 77

[0841] 2-{4-[2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid. mp 200.5-202.5° C.

[0842] Analysis for C₂₁H₁₆Cl₂N₂O₄: Calcd: C, 58.49; H, 3.74; N, 6.50.Found: C, 58.33; H, 3.67; N, 6.29.

Example 78

[0843]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-trifluoromethyl-benzoicacid. mp 130-132° C.

[0844] Analysis for C₂₂H₁₆Cl₂F₃NO₂: Calcd: C, 58.17; H, 3.55; N, 3.08.Found: C, 58.25; H, 3.65; N, 3.05.

Example 79

[0845]2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid. mp>260° C.

Example 80

[0846]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-dimethylamino-benzoicacid. mp 75-80° C.

Example 81

[0847] 2-{4-[2-(3,5-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid.mp 191-194° C.

[0848] Analysis for C₂₁H₁₇Cl₂NO₂: Calcd: C, 65.30; H, 4.44; N, 3.63.Found: C, 65.38; H, 4.29; N, 3.52.

Example 82

[0849]2-(4-{2-[(4aS,8aR)-4-(Octahydro-isoquinolin-2-yl)-phenyl]-ethyl}-phenylamino)-benzoicacid was prepared according to Example 1 using a decahydroisoquinolinealdehyde which was prepared from trans-decahydroisoquinoline andpara-fluorobenzaldehyde under standard reaction conditions. mp 203-206°C.

[0850] Analysis for C₃₀H₃₄N₂020.12H₂O: Calcd: C, 78.89; H, 7.56; N,6.13. Found: C, 78.49; H, 7.58; N, 5.90.

[0851] The following examples are prepared according to the foregoingmethods, or by utilizing standard combinatorial synthetic methodology byreacting halo substituted benzoate esters with a substituted aniline toform the corresponding diarylamine, followed by saponification to thebenzoic acid of Formula 1. The reactions are carried out on 0.15 mmolscale as follows. Solutions of each halo benzoate reactant (0.18 M) intoluene are placed in 2 dram reaction vials. Each aniline reactant isdissolved in anhydrous toluene to give 0.15 M solutions. A Distrimanpipet is used to add 1 mL (0.15 mmol, 1 eq) of each halo benzoatesolution to the appropriate vials containing 1 mL (0.18 mmol, 1.2 eq) ofthe aniline reactants. A catalyst solution is prepared by dissolving0.025 M of Pd₂(dba)₃ (dipalladium-tridibenzylidene acetone) and 0.075 Mof BINAP (2,2-bis(diphenylphosphino)-1,1′-binapthyl) in toluene, and0.25 mL of the catalyst solution is added to each reaction vial. A base,generally cesium carbonate (68 mg, 0.21 mmol, 1.40 eq) is added to eachreaction vial, and the vials are capped and placed in a shaker oven andheated at 100° C. for 48 hours. The reaction mixtures are then cooled,and the reaction solvents are removed by evaporation. The solid residueis suspended in 400 μL of ethyl acetate and filtered to remove allcatalyst. The filtrates are concentrated to dryness by evaporation toprovide compounds of I, wherein the benzoic acid portion is esterified(e.g., benzyl or methyl ester). The esters are dissolved in 500 μL ofTHF/ethanol (1:1 v/v) to which is added 300 μL of 5 M sodium hydroxide.The solutions are shaken for 5 hours at 60° C. and then cooled andconcentrated to dryness by evaporation of the solvents to provide thedesired compounds of Formula I. Typical compounds prepared by thismethod are as follows. The structure of the compounds are generallyconfirmed by mass spectral analysis.

Example 83

[0852] 2-(3′,5′-Dichloro-3-methyl-biphenyl-4-ylamino)-benzoic acid

[0853] MS: 371; MW: 372.2495.

Example 84

[0854] 2-(3′,5′-Dibromo-3-methyl-biphenyl-4-ylamino)-benzoic acid

[0855] MS: 459; MW: 461.1515.

Example 85

[0856] 2-(4-1,3-Benzodioxol-5-yl-2-methyl-phenylamino)-benzoic acid

[0857] MS: 347; MW: 347.3683.

Example 86

[0858] 2-(2,2′,4′-Trichloro-biphenyl-4-ylamino)-benzoic acid

[0859] MS: 391; MW: 392.6678.

Example 87

[0860] 2-(2-Chloro-3′,4′-difluoro-biphenyl-4-ylamino)-benzoic acid

[0861] MS: 359; MW: 359.7578.

Example 88

[0862] 2-(3′-Bromo-2-chloro-biphenyl-4-ylamino)-benzoic acid

[0863] MS: 401; MW: 402.6737.

Example 89

[0864] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid

Example 90

[0865] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-nitro-benzoicacid

Example 91

[0866] 3-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid

Example 92

[0867] 5-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalicacid

Example 93

[0868] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid

Example 94

[0869]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}4,5-dimethoxy-benzoicacid

Example 95

[0870]2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-3-nitro-benzoicacid

Example 96

[0871] 3-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-benzoicacid

Example 97

[0872]5-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-isophthalic acid

Example 98

[0873] 2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-benzoicacid

Example 99

[0874]4-(4-{2-[(4aS,8aR)-4-(Octahydro-isoquinolin-2-yl)-phenyl]-ethyl}-phenylamino)-benzoicacid

Example 100

[0875]2-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-5-methoxy-benzoicacid

Example 101

[0876] 2-{4-[2-(3-Methoxy-phenyl)-ethyl]-phenylamino}-benzoic acid

Example 102

[0877] 2-{4-[2-(3-Bromo-phenyl)-ethyl]-phenylamino}-benzoic acid

Example 103

[0878] 2-{4-[2-(3-Fluoro-phenyl)-ethyl]-phenylamino}-benzoic acid

Example 104

[0879]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoic acid

Example 105

[0880] 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-nicotinic acid

Example 106

[0881]2-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-benzoicacid

Example 107

[0882] 2-{4-[2-(3-Fluoro-4-methyl-phenyl)-ethyl]-phenylamino}-benzoicacid

Example 108

[0883]2-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-5-nitro-benzoicacid

Example 109

[0884] 4-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-benzoic acid

Example 110

[0885]4-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-3-methoxy-6-nitro-benzoicacid

Example 111

[0886]4-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-3-methoxy-benzoicacid

Example 112

[0887]2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoicacid

Example 113

[0888]{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenyl}-(2-methoxy-5-nitro-phenyl)-amine

Example 114

[0889]2-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-3-nitro-benzoicacid

Example 115

[0890] 3-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-benzoic acid

Example 116

[0891] 2-{4-[2-(3,4-Dimethoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;mp 159-161° C.

Example 117

[0892] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acidmonosodium; mp 107-108° C.

Example 118

[0893] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acidmonopotassium; mp>200° C.

Example 119

[0894] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acidcalcium salt (1:1); mp>220° C.

Example 120

[0895] 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoate-2-hydroxy-1,1-bis-hydroxymethyl-ethyl-ammonium; mp185-187° C.

Example 121

[0896]2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-methoxy-benzoicacid; mp 155-158° C.

Example 122

[0897] 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-benzoic acid;mp 184-185° C.

Example 123

[0898] 2-{3-[2-(4-Chloro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp155-157° C.

Example 124

[0899] 2-{3-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-benzoic acid;mp 182-184° C.

Example 125

[0900] 2-{4-(2-(2,4-Dimethoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;mp 180-181° C.

Example 126

[0901] 2-{4-[2-(2-Chloro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp140-143° C.

Example 127

[0902] 2-{4-[2-(2-Hydroxy-phenyl)-ethyl]-phenylamino}-benzoic acid; mp218-219° C.

Example 128

[0903] 2-{4-[2-(3-Chloro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp152-154° C.

Example 129

[0904] 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-benzoic acid; mp200-202° C.

Example 130

[0905] 2-{4-[2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid;mp 181-183° C.

Example 131

[0906] 3-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid;mp 137-138° C.

Example 132

[0907] 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid;mp 214-215° C.

Example 133

[0908] 2-{4-[2-(3,4,5-Trimethoxy-phenyl)-ethyl]-phenylamino}-benzoicacid; mp 146-147° C.

Example 134

[0909] 2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid; mp153-154° C.

Example 135

[0910] 2-{4-[5-(3,4-Dichloro-phenyl)-pentyl]-phenylamino}-benzoic acid;mp 106-108° C.

Example 136

[0911]2-{4-[2-(4-{2-Hydroxycarbonylphenylamino}phenyl)ethyl]-phenylamino}-benzoicacid; MS 451 (M−1).

Example 137

[0912] 2-(3′,5′-Dichloro-biphenyl-4-ylamino)-benzoic acid; mp>220° C.

Example 138

[0913]4-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-2-methoxy-5-nitro-benzoicacid; mp 74-78° C.

Example 139

[0914]2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-5-fluoro-benzoicacid; mp 122-123° C.

Example 140

[0915]5-Amino-2-{4-[5-(3,4-dichloro-phenyl)-pentyl]-phenylamino}-benzoic acid;mp 182-184° C.

Example 141

[0916]N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)-C,C,C-trifluoro-methanesulfonamide;

[0917] MS 531 (M⁻).

Example 142

[0918]N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)-benzenesulfonamide;MS 539.

Example 143

[0919]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid; mp 190-192° C. MS 453 (M−1).

Example 144

[0920] 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalicacid; mp 264-266° C.

Example 145

[0921]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-trifluoromethyl-benzoicacid; mp 134-136° C.; MS 454 (M⁺).

Example 146

[0922]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-trifluoromethyl-benzoicacid; MS 454 (M⁺).

Example 147

[0923]2-({4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-methyl-amino)-5-dimethylamino-benzoicacid; mp 128-131° C.

Example 148

[0924]2-({4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-methyl-amino)-benzoicacid; MS 400 (M⁺).

Example 149

[0925]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-dipropylamino-benzoicacid; MS 485 (M⁺).

Example 150

[0926]5-Dibutylamino-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoicacid; MS 513 (M⁺).

Example 151

[0927]2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-diethylamino-benzoicacid; mp 106-110° C.

Example 152

[0928] 2,2′-[1,2-Ethanediylbis (4,1-phenyleneimino)]bis-benzoic acid

Example 153

[0929]4-[3-[4-(Diethylamino)phenyl]propyl]-N-(2-methoxy-5-nitrophenyl)-benzinamine

Example 154

[0930] 2-{3-[2-(4-Chlorophenyl)ethyl]phenylamino}-benzoic acid

Example 155

[0931] 2-{3-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-benzoic acid

Example 156

[0932] 2-(3-[3-(4-Diethylaminophenyl)propyl]phenylamino)-benzoic acid

Example 157

[0933] 2-{3-[3-(4-Di-n-propylaminophenyl)propyl]phenylamino}-benzoicacid

[0934] The following Examples 158-163 illustrate the use of inventioncompounds as starting materials and intermediates in the synthesis ofother invention compounds and derivatives. The examples illustratereduction of nitro groups to amino groups, alkylation of amino group,and esterification of carboxylic acid groups. These reactions aredepicted in the following generalized Scheme 12.

[0935] where R^(b) and R^(c) are as defined above, and E is an esterforming group such as C₁-C₆ alkyl (e.g., methyl, 2,2,2-trichloroethyl),benzyl, diphenylmethyl, or the like.

Example 158

[0936] 2-{4-[3-(4-Nitrophenyl)propyl]phenylamino}benzoic acid To aslurry of 4-[3-(4-nitrophenyl)propyl]aniline (4.08 g, 15.9 mmol) and2-bromobenzoic acid (3.52 g, 17.5 mmol) in i-PrOH (100 mL) was addedCu(OAc)₂ (87 mg, 0.478 mmol) and KOAc (3.44 g, 35.0 mmol) at roomtemperature. The resulting mixture was allowed to heat under reflux for23 hours, then cooled to room temperature. After removing the solventunder reduced pressure, the residue was diluted with water (100 mL) andbasified with aqueous 1.0 M-NaOH solution to pH 9.0. The aqueous layerwas washed with Et₂O (20 mL, twice) and acidified with aqueous 1.0 M-HClsolution to pH 3.0. The precipitate formed was filtered by suction anddried at 60° C. in vacuo, affording the title compound as a beige solid(5.75 g, 96% yield). mp 150-153° C. MS (Fab): 376 (MH⁺).

Example 159

[0937] 2-{4-[3-(4-Aminophenyl)propyl]phenylamino}benzoic acid

[0938] To a solution of2-{4-[3-(4-nitrophenyl)propyl]phenylamino}benzoic acid (Example 158)(3.0 g, 7.97 mmol) in DMF (40 mL) was added 10% Pd—C (300 mg) at roomtemperature under argon atmosphere. Hydrogen gas (1 atm) was introducedinto the flask and the mixture was stirred for 14 hours at roomtemperature. The reaction mixture was filtered through a Celite pad toremove Pd—C and concentrated in vacuo. The residue was diluted with MeOH(ca. 50 mL) and concentrated in vacuo. This operation was repeated 3times to remove any trace of DMF. The residue was diluted with MeOHagain, and insoluble stuff was removed by filtration. Removing thesolvent of the filtrate in vacuo afforded an oil, which was diluted withCH₃CN (50 mL) and added dropwise water (100 mL) slowly. The precipitateformed was filtered and dried at 60° C. in vacuo, affording the titlecompound as a white solid (2.34 g, 85% yield). mp 110-112° C. MS (Fab):347 (MH⁺).

Example 160

[0939] 2-{4-[3-(4-Aminophenyl)propyl]phenylamino}benzoic acid methylester

[0940] To a solution of2-{4-[3-(4-aminophenyl)propyl]phenylamino}benzoic acid (Example 159)(2.34 g, 6.75 mmol) in MeOH (50 mL) was added concentrated H₂SO₄ (1.0mL) at room temperature. The mixture was stirred under reflux for 3.0days. The reaction was quenched with Et₃N (10 mL) at 5° C., and thesolvent was removed under reduced pressure. The residue was diluted withwater (20 mL) and extracted with Et₂O (20 mL, 4 times). The combinedether layer was washed with water (10 mL) and brine (10 mL), and driedover anhydrous Na₂SO₄. The solvent was removed under reduced pressureand purification by column chromatography afforded crude title compoundas a yellow amorphous material (2.59 g). This material was used withoutfurther purification.

Example 161

[0941] 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acidmethyl ester and 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoicacid methyl ester

[0942] To a solution of the crude ester described above (2.59 g, ca.6.75 mmol) and CH₃CHO (2.0 mL, 35.1 mmol) in CH₃CN (50 mL) was addedNaBH₃CN (1.70 g, 27.0 mmol) at 5° C., and the suspension was stirred for30 minutes while the pH was monitored and aqueous 1.0 M-HCl solution wasadded to maintain the mixture moderately acidic (pH 3.0-4.0). Thereaction mixture was allowed to warm up to room temperature over 1.0hour and then basified with aqueous 1.0 M-NaOH solution to pH 9.0. Thereaction mixture was concentrated under reduced pressure to removeCH₃CN, and the resulting aqueous solution was acidified with aqueous 1.0M-HCl solution to pH 3.0. The aqueous solution was extracted with CHCl₃(20 mL, 3 times), and the combined extract was washed with brine (5 mL).After drying over anhydrous Na₂SO₄, the solvent was removed underreduced pressure and purified by column chromatography (silica gel 60N,n-hexane/CHCl₃/Et₃N 50:98:2). First eluted was the dialkylated productas a yellow amorphous material (1.07 g, 38%).

[0943] MS (Fab): 417 (MH⁺).

[0944] Subsequently eluted was the monoalkylated product as a yellowamorphous material (0.79 g, 30%).

[0945] MS (Fab): 389 (MH⁺).

Example 162

[0946] 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid

[0947] To an emulsion of2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}-benzoic acid methylester (1.68 g, 4.03 mmol) in EtOH (50 mL) was added aqueous 3 M-KOHsolution (4.0 mL, 12.0 mmol) at room temperature, then the mixture wasallowed to heat under reflux for 40 minutes. The reaction mixture wascooled to room temperature and neutralized with aqueous 1.0 M-HClsolution to pH 9.0. The mixture was concentrated under reduced pressureto remove EtOH, and the resulting aqueous solution was extracted withCHCl₃ (50 mL, 3 times). The combined extract was washed with brine (10mL) and dried over anhydrous Na₂SO₄. The solvent was removed underreduced pressure and purification by column chromatography (silica gel60N, conc NH₄OH/MeOH/CHCl₃ 0.2:2:100 to 0.5:5:100) afforded a yellowoil. This oil was diluted with acetone, and the solution wasconcentrated under reduced pressure at room temperature to give thetitle compound as an amorphous solid (1.62 g, 99% for 0.2 hydrate).

[0948] MS (Fab): 403 (MH⁺).

[0949] Analysis for C₂₆H₃₀N₂O₂.20H₂O: Calcd: C, 76.89; H, 7.54; N, 6.90.Found: C, 76.73; H, 7.67; N, 7.10.

Example 163

[0950] 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoic acid

[0951] The title compound was prepared from2-{4-[3-(4-ethylaminophenyl)-propyl]phenylamino}benzoic acid methylester (from Example 161), EtOH (10 mL), and 3 M-KOH solution (1.0 mL)using the procedure described in Example 162. This procedure yielded ayellow solid, 253 mg of the desired product (90% for 0.1 hydrate).

[0952] MS (Fab): 375 (MH⁺).

[0953] Analysis for C₂₄H₂₆N₂O₂.10H₂O: Calcd: C, 76.61; H, 7.02; N, 7.44.Found: C, 76.62; H, 7.06; N, 7.36.

BIOLOGICAL EXAMPLES

[0954] Representative compounds of Formula I have been evaluated inseveral in vitro and in vivo assays which are well-established asindicative of clinical usefulness in treating Alzheimer's disease.

[0955] Amyloid Assays

[0956] BASSR (Beta-Amyloid Self-Seeding Radioassay)

[0957] An Assay for Inhibitors of Self-Seeded Amyloid Fibril Growth

[0958] Materials:

[0959] Stock Solutions:

[0960] Assay Buffer—50 mM sodium phosphate, pH 7.5, 100 mM NaCl, 0.02%NaN₃, 1 M urea (filter and store at 4° C.).

[0961] Soluble Aβ(1-40) peptide (Bachem, Torrance, Calif.)-2.2 mrg/mL indeionized H₂O (stored in aliquots at −20° C., keep on ice when thawed)will self-seed after 1 week storage. Typically, the solution should bestored until no lag phase is seen in the assay.

[0962]¹²⁵I-labeled Aβ (1-40)-150K-350K cpm/mL in 100% acetonitrile—0.1%trifluoroacetic acid (TFA)-1% β-mercaptoethanol (aliquots stored at −20°C.). ¹²⁵I-labeled A, (140) can be made in accordance with the procedureset forth by H. LeVine, II] in Neurobiol. Aging, 16, 755, (1995), whichis hereby incorporated by reference, or this reagent may be purchasedfrom Amersham, Arlington Heights, Ill.

[0963] Final assay conditions: 30 μM soluble A, (140) in deionized waterin assay buffer+20K-50K cpm ¹²⁵I-labeled Aβ (1-40) per assay. Compoundto be tested is dissolved in dimethylsulfoxide (DMSO), typically 5 to 50mM stock, such that the final concentration of DMSO is <1% v/v in theassay.

[0964] Assay: Reaction mixture for 50 assays (on ice) is comprised of0.1 to 0.2 μL of ¹²⁵I-labeled A¹²⁵I-labeled Aβ (140)+1 μL of soluble Aβ(1-40)+13.5 μL assay buffer per assay. The following are the amounts ofthe components of the reaction mixture sufficient for 50 assay wells:

[0965] 5-10 μL ¹²⁵I-labeled Aβ (140) dried down

[0966] 675 ILL assay buffer

[0967] 50 ALL soluble A, (1-40)

[0968] Assay Method

[0969] 1) Prepare reaction mixture above by mixing components andstoring on ice.

[0970] 2) Pipet 14.5 μL of reaction mixture into each of 50 wells on apolypropylene U-bottom 96-well microtiter plate on ice. (Costar 3794).

[0971] 3) Add 1.7 μL of diluted compound to be tested to each well in acolumn of eight, including solvent control. Serial 3-fold dilutions from1 mM (100 μM final) in assay buffer-urea=7 dilutions+zero. Each 96-wellplate can therefore accommodate 11 samples+1 Congo Red control (0.039-5μM final in 2-fold steps).

[0972] 4) Seal the plate with aluminum film (Beckman 538619) andincubate for 10 minutes on ice.

[0973] 5) Raise the temperature to 37° C. and incubate for 3 to 5 hours(depending on the lot of the peptide).

[0974] 6) Remove the aluminum film and add 200 μL/well of ice cold assaybuffer with urea, collecting the radiolabeled fibrils by vacuumfiltration through 0.2 μm pore size GVWP filters in 96-well plates(Millipore MAGV N22, Bedford, Mass.). Determine the radioactivity of thefilters using standard methods well-known to those skilled in the art.

[0975] BASST (Beta-Amyloid Self-seeding, ThioflavinT)

[0976] An Assay for Inhibitors of Self-Seeded Amyloid Fibril Growth

[0977] Methods:

[0978] Materials:

[0979] Stock Solutions:

[0980] Assay Buffer—50 mM sodium phosphate, pH 7.5, 100 mM NaCl, 0.02%NaN₃, 1 M urea (filter and store at 4° C.)

[0981] Soluble Aβ (1-40)-2.2 mg/mL in deionized H₂O (store in aliquotsat −20° C., keep on ice when thawed) will self-seed after 1 weekstorage. Typically, the solution should be stored until no lag phase isseen in the assay.

[0982] Final assay conditions: 30 μM soluble Aβ (1-40) in deionizedwater in assay buffer. Compound to be tested is dissolved in DMSO,typically 5 to 50 mM stock, such that the final concentration of DMSO is<1% v/v in the assay.

[0983] Assay: Reaction mixture for 50 assays (on ice) comprised of 1 μLof soluble Aβ (140)+13.5 μL assay buffer per assay. The following arethe amounts of the components of the reaction mixture that result ineach of the 50 assay wells:

[0984] 50 μL soluble Aβ (140)

[0985] 675 mL assay buffer

[0986] Assay Method

[0987] 1) Prepare the reaction mix above by mixing the components andstoring on ice.

[0988] 2) Pipet 14.5 μL of reaction mixture into each of 50 wells of apolystyrene U-bottom 96-well microtiter plate (Corning 25881-96) on ice.

[0989] 3) Add 1.7 μL of diluted compound to be tested to each well in acolumn of eight, including solvent control. Serial 3-fold dilutions from1 mM (100 JIM final) in assay buffer-urea=7 dilutions+zero. Each 96-wellplate can therefore accommodate 11 samples+1 Congo Red control (0.039-5μM final in 2-fold steps).

[0990] 4) Seal the plate with aluminum film and incubate for 10 minuteson ice.

[0991] 5) Raise the temperature to 37° C. and incubate for 3 to 5 hours(depends on the lot of the peptide).

[0992] 6) Remove the aluminum film and add 250 μL/well of 5 μMthioflavin T (ThT) [T-3516, Sigma-Aldrich] in 50 mM glycine-NaOH, pH8.5. Read fluorescence on a plate reader (ex=440 nm/20 nm; em=485 nm/20nm) within 5 minutes.

[0993] BAPA (Beta-Amyloid Peptide Aggregation)

[0994] This assay is used to provide a measure of inhibition by acompound against the aggregation behavior of the beta amyloid peptide.

[0995] The purpose of this assays is to provide a higher volume methodof assaying the amount of beta amyloid aggregation using an endpointassay based on filtration. In this assay, hexafluoroisopropanol (HFIP)is used to break down the initial amyloid peptide to a monomer state anduse a concentration of 33 μM which is high enough so that aggregationwill occur at pH 6.0 in several hours.

[0996] Methods:

[0997] β-Amyloid Peptide Aggregation. RH 6.0 (BAPA)

[0998] In a 96-well plate (Costar 3794), we add 25 μL 50 mM PhosphateBuffer, pH 6.0, 10 μL 0.5 mg/mL AP (140) peptide in 20% HFIP+0.1 μLassay radioiodinated ¹²⁵I Aβ (1-40) [¹²⁵I Aβ (1-40)], and 1 μL of thecompound to be tested starting at 50 mM with a concentration of DMSO<1%.Then, we incubate for 2 to 4 hours at room temperature. We stop thereaction with 200 μL of 50 mM phosphate buffer, pH 6.0, and filter itthrough a 0.2 μm 96-well filter plate (Millipore MAGU N22). We wash thefilter plate with 100 μL of the same phosphate buffer. Aggregation wasdetected on a Microbeta counter after impregnating the filters withMeltilex (1450-441) and is corrected for background.

[0999] BATYM Assay

[1000] Methods:

[1001] Required AP (1-42) (California Peptide) was dried from itshexafluoroisopropanol (HFIP) stock solution. The AP (142) was dissolvedin dimethylsulfoxide (DMSO) and then mixed with phosphate bufferedsaline (PBS) (pH 7.4). The mixed AO (1-42) solution was filtered with a0.2 μm Omnipore membrane syringe filter (Millipore, Bedford, Mass.). Thecompound to be tested in DMSO (50 times concentrate) was put into eachwell (0.5 mL/well) of a 96-well plate. The A (1-42) solution was addedinto each well (24.5 μl/well). The plate was centrifuged at 1,000 g for5 minutes and incubated at 37° C. for 1 day (Aβ 1-42; finalconcentration 100 μM).

[1002] After incubation Thioflavin T (ThT) (30 lIM) solution inglycine-NaOH buffer (pH 8.5, 50 mM) was added into each well (250μL/well), fluorescence was measured (ex=440/20 nm, em=485/20 nm) using afluorescence plate reader. The inhibitory activity was, calculated asthe reduction of fluorescence with the following formula:

[1003] Inhibition(%)={(F(Aβ)−F(Aβ+compound)}/{F(Aβ)−F(solvent+compound)}×100

[1004] The IC₅₀s were calculated by a curve fitting program using thefollowing equation. The data were obtained from two differentexperiments in triplicate.

[1005] Inhibition(x)=100-100/{I+(x/IC₅₀)_(n)},

[1006] x=Concentration of tested compound (M),

[1007] IC₅₀=(M),

[1008] n=Hill coefficient.

[1009] Representative compounds of Formula I have exhibited inhibitoryactivities (IC₅₀) ranging from 0.1 μM to greater than 100 μM in theforegoing assays.

[1010] The results of these assays for specific and representativecompounds of the present invention are shown in Table I below. TABLE 1β-Amyloid Inhibitory Activity of Compounds of Formula I Example BASSRBASST BATYM BAPA No. (IC₅₀ = μM) (IC₅₀ = μM) (IC₅₀ = μM) (IC₅₀ = μM) 110 (P), >100 (P) 2, 4, 30, 10 (P) 50, 58.8 (P) 60 (P), >100 (P)(6×), >100 (Q), 3(Q) 57.8 (Q) 86 (Q), >100 (R), >100 (R) >60 (R), >100(S), 11 (S), 11 (T) >60 (S), 52 (T) 6(Z) 11 (T) >100 (Z) 2 2.2, 4.1,4.1, 1, 1.5 (P) 6.52 (P) 70 (P) 12, 4.5 3 4.5, 5, 5 2 (P) 11.7 (P) >60(P) (all 3 V-shaped) 3 (Q) (P) 15 (ppt), 5(Q) 4 30, 3, 4, 8 26.3, 30.767 >100 (3×) 5 70, >100 4.5 10 74 6 15, 21, 20, 40 4, 1, 3 21.5 >60 718, 13, 12, 20 2 8.83 39 8 15, 15, 18, 15 3, >100 7.17 9 20 (ppt), 30,1, 2 (P) 20.1, 28.2 (P) 75 (P) 52, 40 (P) 38.6 (R) 10 70, 50 4 75.7 6711 18 (ppt), 1, 1, 3 (P) 5.62 (P) 23 (P) 20 (ppt), 1, 0.8 (Q) 6.78 (Q) 9(Q) 20 (2×), >100 (P) >100, 21, 30 (Q) 12 20 (4×) 1, 1 3.93 >60 1321, >100, 0.9 6.41 6 20 (ppt), 15 (ppt), >100 14 18 (ppt), 8, 1.010.9 >10 6 (ppt), 7 (ppt) (V-shaped) 15 100 (3×) P 1 (P) 8.52 (P) >60(P) 100, 16 1.2 (Q) 7.26 (Q) 7 (Q) (V-shaped) 7.07 (Q) 12, 15, 11 (Q) 1618, 7.5, 10 (P) 3, 0, 3 (P) 12 (P) 13 (P) 70, 32, 42 (Q) 1.1, 0.8, 0.6(Q) 10.3 (Q) 17 >100 (ppt) (3×) 6.2 64.5 >60 (Q), 41 (R) 18 >100 (5×)(P) 30, >100 (P) >100 (P) 9, >40, 53 (P), 12 19 3, 4, >100, 2.2 >100, 1,1, 1.5 31.0, 34.0 >60, 43 20 4.2 6 68.6 22 21 3 4 62.7 26 22 3 9 >100 2423 20 2 >100 17 24 >100 20 >100 91 25 >100 4 21.1 47 26 >100 1 >100 5727 >100 3 19.8 74 28 >100 5 42.3 27 29 >100 4 38.1 30 30 30, 20 4, 275.3 38 31 >100 1 22.6 86 32 >100 1 29.2 96 33 >100 >100 >100 >10 34 453 45.0 48 35 >100 100 >100 154 36 >100 >100 >100 149 37 >100 0.8 30.2 2538 20, 10 (V) 3 23.4 184 39 >100 20 >100 21 40 >100 3.0 >100 53 41 >1005 49.7 42 42 >100 2 55.6 30 43 >100 0.3 24.2 63 44 >100 1 26.5 5245 >100 1 21.5 32 46 >100 6 34.3 47 >100 2 38.2 48 25 10 >10049 >100 >100 >100 50 >100 >100 >100 51 85 0.8 39.1 52 75 0.5 36.553 >100 0.3 30.0 54 >100 0.4 43.9 55 12 2 5.1 101 56 >100 3 11.5 30 574.8 1.5 4.0 50 58 3.5 1 5.1 60 59 >100 >100 >100 3 60 >100 3 40.7 8 6118, 7.5, 10 3, 0.3 12 13 62 >100 1.5 8.98 63 15, 15, 18 (ppt) 1 9.43 4564 >100 5 35 >100 65 60, 80 1.5 15.9 >100 (V-shaped) 66 >100 (ppt), 2.150.1 >100 >100 (ppt) 67 41 4 13.3 >60 68 >100, >100 1 >100 110 69 2(V-shaped), 0.8 11.7 58 3.5 (ppt) 70 20, 100 10 >100 65 71 >100 3 >60 7240, 15, 12 2, 2.5 74.8 >60, >60 73 25, 35, 40 0.3 9.43 >60 74 6, 18, 19,18 0.3, 0.5 8.36 >60 75 >100 2.2 46.2 >60 76 3 0.5 8.59 >60 77 18, 15 8,0.3 9.49 >60 78 70 0.1 >100 8 79 3.1, 50, 38, 70, 1, 0.3, 0.3, 0.3 9.1451 70, 30, 40 80 >100 4 24.8 >60 81 >100 15 48.4 73 82 >100, >100, >1002, 0.3, 0.3 83 >100 >100 9, 47, 29 84 >100 >100 5, 40, 21 85 >100 18 8,77, 45 86 40 18 >10, 89, 37 87 >100 50 >10, 15, 32 88 >100 10 >10, 37,27 116 >100, >100 18, 30 96 117 >100 3 61.3 >100 118 >100, >100 6 >60119 >100 3 >60 120 >100 3 >60 121 >100, >100 1 122 >100 2 >100 >60123 >100 (3 ×), 14 3, 3 70.8 4, 18, >100, 3.2, 4 (Q) 85.2 (Q) >60(Q) >100 (Q) 124 >100 10 62.7 125 82 10 >100 80 126 >100, >100 4, 5 8463 30, 100 (Q) 10, 4 (Q) 73.9 (Q) >60 (Q) 127 >100 (ppt) 10 >100 67128 >100 (ppt) (4 ×) 10, 41, 6 75 60 11, >100 (3 ×) 15, 20, 10; 7.5 (Q)7, 3, 3 (Q) >60 (Q) >60 (Q) 15, >100 (3 ×) Q 129 1 (V-shaped) (2 ×) 10,3, 2, 2 >100 >102 >100 (ppt) 130 >100 (3 ×) 2, >100, 50 47.5 238131 >100 10 93.5 >60 132 >100 10 >100 60 133 >100 >100 >100 >60 134 >1002 36.5 >60 135 >100 1.2 31.2 >60 136 >100 3 >100 53 137 >100, >100 3 52141 >100 7 56.7 >50 142 >100 2.1 26.9 55 143 >100 (4 ×) 40, 30 >1002, >60, >60 144 15, 25 40 >100 114 145 10, 40, 30 4 56.8 9 146 >10030 >100 >60 147 >100 10 93.4 >60 148 >100 >100 149 >100 >100 >100 >60150 >100 10 >100 76 151 >100, >100 5, >100 >100 108 154 >100 3, 30 70.8155 >100 3 44.6 156 27.8 157 25.9

[1011] A letter in parentheses after particular value indicates theparticular synthetic lot of the compound tested. The terms “P,” “Q,”“R,” “S,” “T,” and “Z” designate different lots of the same compound.For example, 10 (P) indicates that compound tested was from Lot P. If nolot is specified, the lot of the compound was Lot P.

[1012] The abbreviation “ppt” means precipitate and indicates that aprecipitate formed at the indicated concentration. In addition, the term“V-shaped” means that inhibition was observed followed by precipitation.

[1013] A value followed by a number and × (i.e., 4×) means that thecompound was tested four times, and each time the result was the same.

[1014] The invention compounds have also shown good activity in standardin vivo assays commonly used to evaluate agents to treat diseasesrelated to aggregation of amyloid proteins, especially Alzheimer'sdisease and other amyloidoses. In one assay, amyloid protein is inducedinto the spleen of mice by subcutaneous injections of silver nitrate,Freund's complete adjuvant, and an intravenous injection of amyloidenhancing factor. Silver nitrate is administered each day through Day11. Test compounds are administered to the mice daily starting on Day 1through Day 11. On Day 12, the animals are sacrificed, and the spleensare removed, histologically prepared, stained with Congo red, and thepercent area of the spleen occupied by birefringent, Congo red-stainedamyloid is quantitated microscopically. Invention compounds evaluated inthis test have inhibited splenic amyloid deposition by up to 70%relative to untreated controls.

[1015] Another in vivo assay in which the invention compounds have beenevaluated uses transgenic mice. The mice bear a human β-amyloidprecursor protein transgene with a prion promoter and are described byHsiao et al., “Correlative memory deficits, Aβ elevation, and amyloidplaques in transgenic mice,” Science 1966;274:99-102. These transgenicmice develop O-amyloid deposits at about 9 months of age. By 15 months,diffuse and compact senile plaques are abundant, primarily in theneocortex, olfactory bulb, and hippocampus. Invention compounds areadministered orally to the mice beginning at the age of 8 months Oustprior to the onset of amyloid deposits) and continuing for severalmonths (up to about age 14-18 months). The animals are then sacrificed,and the brains are removed. The amount of amyloid in the brain isquantitated both histologically and biochemically. Invention compoundsevaluated in this model have inhibited amyloid accumulation in thecortex and hippocarrpus by up to 49% relative to untreated controls.

[1016] The above data establishes that representative inventioncompounds are active in standard assays used to measure inhibition ofprotein aggregation. The compounds exhibit excellent specificity, forexample, as shown in the BASST assay, as well as the BATYM and BAPAassays. The compounds are thus useful to clinically inhibit amyloidprotein aggregation and to image amyloid deposits for diagnostic use.The compounds will be used in the form of pharmaceutical formulations,and the following examples illustrate typical compositions.

Example 164

[1017] Tablet Formulation Ingredient Amount Compound of Example 1  50 mgLactose  80 mg Cornstarch (for mix)  10 mg Cornstarch (for paste)  8 mgMagnesium Stearate (1%)  2 mg 150 mg

[1018] The compound of Example 1 is mixed with the lactose andcornstarch (for mix) and blended to uniformity to a powder. Thecornstarch (for paste) is suspended in 6 mL of water and heated withstirring to form a paste. The paste is added to the mixed powder, andthe mixture is granulated. The wet granules are passed through a No. 8hard screen and dried at 50° C. The mixture is lubricated with 1%magnesium stearate and compressed into a tablet. The tablets areadministered to a patient at the rate of 1 to 4 each day for preventionof amyloid protein aggregation and treatment of Alzheimer's disease.

Example 165

[1019] Parenteral Solution

[1020] In a solution of 700 mL of propylene glycol and 200 mL of waterfor injection is added 20.0 g of Compound No. 19 (Example 19). Themixture is stirred and the pH is adjusted to 5.5 with hydrochloric acid.The volume is adjusted to 1000 mL with water for injection. The solutionis sterilized, filled into 5.0 mL ampoules, each containing 2.0 mL (40mg of Compound No. 19), and sealed under nitrogen. The solution isadministered by injection to a patient suffering from medullarycarcinoma of the thyroid and in need of treatment.

Example 166

[1021] Patch Formulation

[1022] Ten milligrams of2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid is mixedwith 1 mL of propylene glycol and 2 mg of acrylic-based polymer adhesivecontaining a resinous cross-linking agent. The mixture is applied to animpermeable backing (30 cm²) and applied to the upper back of a patientfor sustained release treatment of amyloid polyneuropathy.

[1023] The invention and the manner and process of making and using it,are now described in such full, clear, concise, and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

1. A method of treating Alzheimer's disease, the method comprisingadministering to a patient having Alzheimer's disease a therapeuticallyeffective amount of a compound of Formula I

wherein R^(a) is hydrogen, C₁-C₆ alkyl, or

n is 0 to 5 inclusive; R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are independentlyhydrogen, halogen, —OH, —NH₂, NR^(b)R^(c), —CO₂H, —CO₂C₁-C₆ alkyl, —NO₂,—OC₁-C₁₂ alkyl, —C₁-C₈ alkyl, —CF₃, —CN, —OCH₂ phenyl, —OCH₂-substitutedphenyl, —(CH₂)_(m)-phenyl, —O-phenyl, —O-substituted phenyl,—CH═CH-phenyl, —O(CH₂)_(p)NR^(b)R^(c),

—NH(CH₂)_(p)NR^(b)R^(c), —N(C₁-C₆alkyl)(CH₂)_(p)NR^(b)R^(c),

R⁸ is COOH, tetrazolyl, —SO₂R^(d), or —CONHSO₂R^(d); R^(b) and R^(C) areindependently hydrogen, —C₁-C₆ alkyl, —(CH₂)_(m)-phenyl, or R^(b) andR^(c) taken together with the nitrogen atom to which they are attachedform a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl,piperazinyl, 4-C₁-C₆ alkylpiperazinyl, morpholino, thiomorpholino,decahydroisoquinoline, or pyrazolyl; R^(d) is hydrogen, —C₁-C₆ alkyl,—CF₃, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CHor N; R¹ and R², when adjacent to one another, can be methylene-dioxy;or the pharmaceutically acceptable salts thereof.
 2. The method of claim1 wherein R^(a) is hydrogen; n is 2; and R³ and R⁴ are hydrogen.
 3. Themethod of claim 1 wherein R^(a) is hydrogen; R³ and R⁴ are hydrogen; andn is 2 to 5 inclusive.
 4. The method of claim 1 wherein R^(a) ishydrogen; n is 2; R³ and R⁴ are hydrogen; and R¹, R², and R⁷ areindependently chlorine, —N(CH₂CH₃)₂, —OH, CH₃—, fluorine, —CF₃, phenyl,hydrogen, —OCH₂ phenyl, —O(CH₂)₃N(CH₃)₂, —O phenyl, —O(CH₂)₇CH₃,—CH(CH₂OCH₂CH₃)₂, pyrrolyl, —CH═CH-phenyl,

 —N[(CH₂)₃CH₃]₂, substituted phenyl, —OCH₂— substituted phenyl,pyrrozolyl, or —N(phenyl)₂.
 5. The method of claim 1 wherein R^(a) ishydrogen; n is 3, 4, or 5; R³ and R⁴ are hydrogen; and R¹, R², and R⁷are independently chlorine or hydrogen.
 6. The method of claim 1 whereinR^(a) is hydrogen; n is 2; R³ and R⁴ are hydrogen; and R⁵, R⁶, and R⁸are independently hydrogen, —CO₂H, —NO₂, —OCH₃, imidazolyl, —CN,fluorine, —CH₃, —CF₃, halogen, —NH—C₁-C₆ alkyl, —N(C₁-C₆alkyl)₂, —NH₂,or pyrrolyl.
 7. The method of claim 1 wherein R^(a) is hydrogen; n is 2;R³ and R⁴ are hydrogen; and R⁵ is —CO₂H.
 8. A method of treatingAlzheimer's disease, the method comprising administering to a patienthaving Alzheimer's disease a therapeutically effective amount of acompound of Formula I

wherein R^(a) is hydrogen; n is 1 to 5 inclusive; R³ and R⁴ arehydrogen; R¹, R⁷, and R² are independently chlorine, —N(CH₂CH₃)₂, —OH,CH₃—, fluorine, —CF₃, phenyl, hydrogen, —OCH₂ phenyl, —O(CH₂)₃N(CH₃)₂,—O phenyl, —O(CH₂)₇CH₃, —CH(CH₂OCH₂CH₃)₂, pyrrolyl, —CH═CH-phenyl,—N[(CH₂)₃CH₃]2, substituted phenyl, —OCH₂-substituted phenyl, pyrazolyl,or —N(phenyl)₂; R⁵ and R⁶ are independently hydrogen, —CO₂H, —NO₂,—OCH₃, imidazolyl, —CN, fluorine, —CH₃, —CF₃, or pyrrolyl; R⁸ is COOH ortetrazolyl; or the pharmaceutically acceptable salts thereof.
 9. Themethod of claim 1 wherein the compound of Formula I is:2-[[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl]amino-benzoic acid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid;2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-4-methoxy-5-nitrobenzoicacid; 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid;2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid;2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid;2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoicacid;2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoicacid; 2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino}benzoic acid;2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid;2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoic acid;2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}-3,5-dinitrobenzoic acid;2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid;2-{4-[5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoicacid; 2-[4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid;2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid;2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid;2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoicacid; 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid;5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid;2-(4-Phenethyl-phenylamino)-benzoic acid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-terephthalicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoicacid; 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methanesulfonyl-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-imidazol-1-yl-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-nitro-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-nitro-benzoicacid; 5-Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4,6-difluoro-benzoicacid;6-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-2,3-difluoro-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-fluoro-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-fluoro-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-methyl-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-fluoro-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3,5-difluoro-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-trifluoromethyl-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-trifluoromethyl-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-pyrrol-1-yl-benzoicacid; 2-{4-[2-(4-Benzyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl]-ethyl}-phenylamino)-benzoicacid; 2-{4-[2-(4-Diethylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Octyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;2-(4-{2-[4-(2-Ethoxy-1-ethoxymethyl-ethyl)-phenyl]-ethyl}-phenylamino)-benzoicacid; 2-{4-[2-(4-Pyrrol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Styryl-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4′-Ethyl-biphenyl-4-yl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Octyl-phenyl)-ethyl]-phenylamino}-benzoic acid;2-(4-{2-[3-(3,5-Dichloro-phenoxy)-phenyl]-ethyl}-phenylamino)-benzoicacid;2-(4-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoicacid; 2-{4-[2-(4-Pyrazol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;2-(4-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoicacid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-amino-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid; 2-{4-[2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid;2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid;2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid;2-[[4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]phenyl]amino-benzoicacid; or 2-[4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.
 10. A methodof inhibiting the aggregation of amyloid proteins to form amyloiddeposits, the method comprising administering to a patient in need ofinhibition of the aggregation of amyloid protein an amyloid proteinaggregation inhibiting amount of a compound of Formula I

wherein R^(a) is hydrogen, C₁-C₆ alkyl, or

n is 0 to 5 inclusive; R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are independentlyhydrogen, halogen, —OH, —NH₂, NR^(b)R^(c), —CO₂H, —CO₂C₁-C₆ alkyl, —NO₂,—OC₁-C₁₂ alkyl, —C₁-C₈ alkyl, —CF₃, —CN, —OCH₂ phenyl, —OCH₂-substitutedphenyl, —(CH₂)_(m)-phenyl, —O-phenyl, —O-substituted phenyl,—CH═CH-phenyl, —O(CH₂)_(p)NR^(b)R^(c),

—NH(CH₂)_(p)NR^(b)R^(c), —N(C₁-C₆alkyl)(CH₂)_(p)NR^(b)R^(c),

R⁸ is COOH, tetrazolyl, —SO₂R^(d), or —CONHSO₂R^(d); R^(b) and R^(c) areindependently hydrogen, —C₁-C₆ alkyl, —(CH₂)_(m)-phenyl, or R^(b) andR^(C) taken together with the nitrogen atom to which they are attachedform a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl,piperazinyl, 4-C₁-C₆ alkylpiperazinyl, morpholino, thiomorpholino,decahydroisoquinoline, or pyrazolyl; R^(d) is hydrogen, —C₁-C₆ alkyl,—CF₃, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is N;R¹ and R², when adjacent to one another, can be methylene-dioxy; or thepharmaceutically acceptable salts thereof.
 11. The method of claim 10wherein R^(a) is hydrogen; n is 2; and R³ and R⁴ are hydrogen.
 12. Themethod of claim 10 wherein R^(a) is hydrogen; R³ and R⁴ are hydrogen;and n is 2 to 5 inclusive.
 13. The method of claim 10 wherein R^(a) ishydrogen; n is 2; R³ and R⁴ are hydrogen; and R¹, R², and R⁷ areindependently chlorine, —N(CH₂CH₃)₂, —OH, CH₃—, fluorine, —CF₃, phenyl,hydrogen, —OCH₂ phenyl, —O(CH₂)₃N(CH₃)₂, —O phenyl, —O(CH₂)₇CH₃,—CH(CH₂OCH₂CH₃)₂, pyrrolyl, —CH═CH-phenyl,

—N[(CH₂)₃CH₃]₂, substituted phenyl, —OCH₂-substituted phenyl, pyrazolyl,or —N(phenyl)₂.
 14. The method of claim 10 wherein R^(a) is hydrogen; nis 3, 4, or 5; R³ and R⁴ are hydrogen; and R¹, R², and R⁷ areindependently chlorine or hydrogen.
 15. The method of claim 10 whereinR^(a) is hydrogen; n is 2; R³ and R⁴ are hydrogen; and R⁵ and R⁶ areindependently hydrogen, —CO₂H, —NO₂, —OCH₃, imidazolyl, —CN, fluorine,—CH₃, —CF₃, halogen, —NH—C₁-C₆ alkyl, —N(C₁-C₆alkyl)₂, —NH₂, orpyrrolyl.
 16. The method of claim 10 wherein R^(a) is hydrogen; n is 2;R³ and R⁴ are hydrogen; and R⁸ is —CO₂H.
 17. A method of inhibiting theaggregation of amyloid proteins to form amyloid deposits, the methodcomprising administering to a patient in need of inhibition of theaggregation of amyloid protein an amyloid protein aggregation inhibitingamount of a compound of Formula I

wherein R^(a) is hydrogen; n is 1 to 5 inclusive; R³ and R⁴ arehydrogen; R¹, R⁷, and R² are independently chlorine, —N(CH₂CH₃)₂, —OH,CH₃—, fluorine, —CF₃, phenyl, hydrogen, —OCH₂ phenyl, —O(CH₂)₃N(CH₃)₂,—O phenyl, —O(CH₂)₇CH₃, —CH(CH₂OCH₂CH₃)₂, pyrrolyl, —CH═CH-phenyl,—N[(CH₂)₃CH₃]2, substituted phenyl, —OCH₂-substituted phenyl, pyrazolyl,or —N(phenyl)₂; R⁵ and R⁶ are independently hydrogen, —CO₂H, —NO₂,—OCH₃, imidazolyl, —CN, fluorine, —CH₃, —CF₃, or pyrrolyl; R⁸ is COOH ortetrazolyl; A is N; R¹ and R², when adjacent to one another, can bemethylene-dioxy; or the pharmaceutically acceptable salts thereof.18-21. (Cancelled).
 22. The compounds:4-{4-[2-(3,4-Dicloro-phenyl)-ethyl]-phenylamino}-nicotinic acid. 23-27.(Cancelled).
 28. A method of imaging amyloid deposits, the methodcomprising: a. introducing into a patient a detectable quantity of alabeled compound having the Formula I or a pharmaceutically acceptablesalt thereof:

 wherein R^(a) is hydrogen, C₁-C₆ alkyl, or

n is 0 to 5 inclusive; R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are independentlyhydrogen, halogen, —OH, —NH₂, NR^(b)R^(c), —CO₂H, —CO₂C₁-C₆ alkyl, —NO₂,—OC₁-C₁₂ alkyl, —C₁-C₈ alkyl, —CF₃, —CN, —OCH₂ phenyl, —OCH₂-substitutedphenyl, —(CH₂)_(m)-phenyl, —O-phenyl, —O-substituted phenyl,—CH═CH-phenyl, —O(CH₂)_(p)NR^(b)R^(c),

—NH(CH₂)_(p)NR^(b)R^(c), —N(C₁-C₆alkyl)(CH₂)_(p)NR^(b)R^(c),

R⁸ is COOH, tetrazolyl, —SO₂R^(d), or —CONHSO₂R^(d); R^(b) and R^(c) areindependently hydrogen, —C₁-C₆ alkyl, —(CH₂)_(m)-phenyl, or R^(b) andR^(c) taken together with the nitrogen atom to which they are attachedform a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl,piperazinyl, 4-C₁-C₆ alkylpiperazinyl, morpholino, thiomorpholino,decahydroisoquinoline, or pyrazolyl; R^(d) is hydrogen, —C₁-C₆ alkyl,—CF₃, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CHor N; R¹ and R², when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof. b. allowingsufficient time for the labeled compound to become associated withamyloid deposits; and c. detecting the labeled compound associated withthe amyloid deposits.
 29. The method of claim 28 wherein the patient hasor is suspected to have Alzheimer's disease.
 30. The method of claim 28wherein the labeled compound is a radio labeled compound.
 31. The methodof claim 28 wherein the labeled compound is detected using MRI. 32-41.(Cancelled).
 42. A compound of Formula I.

wherein R^(a) is hydrogen, C₁-C₆ alkyl, or

n is 0 to 5 inclusive; R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are independentlyhydrogen, halogen, —OH, —NH₂, NR^(b)R^(c), —CO₂H, —CO₂C₁-C₆ alkyl, —NO₂,—OC₁-C₁₂ alkyl, —C₁-C₈ alkyl, —CF₃, —CN, —OCH₂ phenyl, —OCH₂-substitutedphenyl, —(CH₂)_(m)-phenyl, —O-phenyl, —O-substituted phenyl,—CH═CH-phenyl, —O(CH₂)_(p)NR^(b)R^(c),

—NH(CH₂)_(p)NR^(b)R^(c), —N(C₁-C₆alkyl)(CH₂)_(p)NR^(b)R^(c),

R⁸ is COOH, tetrazolyl, —SO₂R^(d), or —CONHSO₂R^(d); R^(b) and R^(c) areindependently hydrogen, —C₁-C₆ alkyl, —(CH₂)_(m)-phenyl; or R^(b) andR^(c) taken together with the nitrogen atom to which they are attachedform a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl,piperazinyl, 4-C₁-C₆ alkylpiperazinyl, morpholino, thiomorpholino,decahydroisoquinoline, or pyrazolyl; R^(d) is hydrogen, —C₁-C₆ alkyl,—CF₃, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CHor N; R¹ and R², when adjacent to one another, can be methylene-dioxy;or the pharmaceutically acceptable salts thereof.
 43. A pharmaceuticalformulation comprising a compound of claim 42 admixed with apharmaceutically acceptable diluent, excipient, or carrier therefor.